Identification of Hydrolyzable Tannins (Punicalagin, Punicalin and Geraniin) as Novel inhibitors of Hepatitis B Virus Covalently Closed Circular DNA

The development of new agents to target HBV cccDNA is urgently needed because of the limitations of current available drugs for treatment of hepatitis B. By using a cell-based assay in which the production of HBeAg is in a cccDNA-dependent manner, we screened a compound library derived from Chinese herbal remedies for inhibitors against HBV cccDNA. Three hydrolyzable tannins, specifically punicalagin, punicalin and geraniin, emerged as novel anti-HBV agents. These compounds significantly reduced the production of secreted HBeAg and cccDNA in a dose-dependent manner in our assay, without dramatic alteration of viral DNA replication. Furthermore, punicalagin did not affect precore/core promoter activity, pgRNA transcription, core protein expression, or HBsAg secretion. By employing the cell-based cccDNA accumulation and stability assay, we found that these tannins significantly inhibited the establishment of cccDNA and modestly facilitated the degradation of preexisting cccDNA. Collectively, our results suggest that hydrolyzable tannins inhibit HBV cccDNA production via a dual mechanism through preventing the formation of cccDNA and promoting cccDNA decay, although the latter effect is rather minor. These hydrolyzable tannins may serve as lead compounds for the development of new agents to cure HBV infection

Mendelian randomization shows causal effects of birth weight and childhood body mass index on the risk of frailty

BackgroundThe association between birth weight and childhood body mass index (BMI) and frailty has been extensively studied, but it is currently unclear whether this relationship is causal.MethodsWe utilized a two-sample Mendelian randomization (MR) methodology to investigate the causal effects of birth weight and childhood BMI on the risk of frailty. Instrumental variables (p < 5E-08) strongly associated with own birth weight (N = 298,142 infants), offspring birth weight (N = 210,267 mothers), and childhood BMI (N = 39,620) were identified from large-scale genomic data from genome-wide association studies (GWAS). The frailty status was assessed using the frailty index, which was derived from comprehensive geriatric assessments of older adults within the UK Biobank and the TwinGene database (N = 175,226).ResultsGenetically predicted one standard deviation (SD) increase in own birth weight, but not offspring birth weight (maternal-specific), was linked to a decreased frailty index (β per SD increase = −0.068, 95%CI = −0.106 to −0.030, p = 3.92E-04). Conversely, genetically predicted one SD increase in childhood BMI was associated with an elevated frailty index (β per SD increase = 0.080, 95%CI = 0.046 to 0.114, p = 3.43E-06) with good statistical power (99.8%). The findings remained consistent across sensitivity analyses and showed no horizontal pleiotropy (p > 0.05).ConclusionThis MR study provides evidence supporting a causal relationship between lower birth weight, higher childhood BMI, and an increased risk of frailty

The properties of horizontal magnetic elements in quiet solar intranetwork

Using the data observed by the Solar Optical Telescope/Spectro-Polarimeter aboard the Hinode satellite, the horizontal and vertical fields are derived from the wavelength-integrated measures of Zeeman-induced linear and circular polarizations. The quiet intranetwork regions are pervaded by horizontal magnetic elements. We categorize the horizontal intranetwork magnetic elements into two types: one is the non-isolated element which is accompanied by the vertical magnetic elements during its evolution; another is the isolated element which is not accompanied by the vertical magnetic elements. We identify 446 horizontal intranetwork magnetic elements, among them 87 elements are isolated and 359 are non-isolated. Quantitative measurements reveal that the isolated elements have relatively weaker horizontal magnetic fields, almost equal size, and shorter lifetime comparing with the non-isolated elements. Most non-isolated horizontal intranetwork magnetic elements are identified to associate with the emergence of Omega-shaped flux loops. A few non-isolated elements seem to indicate scenarios of submergence of Omega loops or emergence of U-like loops. There is a positive correlation between the lifetime and the size for both the isolated and non-isolated HIFs. It is also found that there is also positive correlation between the lifetime and the magnetic flux density for non-isolated HIFs, but no correlation for isolated HIFs. Even though the horizontal elements show lower magnetic flux density, they could carry the total magnetic flux in the order of magnitude close to 10^25 Mx to the solar surface each day.Comment: 10 figures, 25 pages. ApJ, in pres

Observation of room-temperature ferroelectricity in elemental Te nanowires

Ferroelectrics are essential in low-dimensional memory devices for multi-bit storage and high-density integration. A polar structure is a necessary premise for ferroelectricity, mainly existing in compounds. However, it is usually rare in elemental materials, causing a lack of spontaneous electric polarization. Here, we report an unexpected room-temperature ferroelectricity in few-chain Te nanowires. Out-of-plane ferroelectric loops and domain reversal are observed by piezoresponse force microscopy. Through density functional theory, we attribute the ferroelectricity to the ion-displacement created by the interlayer interaction between lone pair electrons. Ferroelectric polarization can induce a strong field effect on the transport along the Te chain, supporting a self-gated field-effect transistor. It enables a nonvolatile memory with high in-plane mobility, zero supply voltage, multilevel resistive states, and a high on/off ratio. Our work provides new opportunities for elemental ferroelectrics with polar structures and paves a way towards applications such as low-power dissipation electronics and computing-in-memory devices

Glot500: Scaling Multilingual Corpora and Language Models to 500 Languages

The NLP community has mainly focused on scaling Large Language Models (LLMs) vertically, i.e., making them better for about 100 languages. We instead scale LLMs horizontally: we create, through continued pretraining, Glot500-m, an LLM that covers 511 predominantly low-resource languages. An important part of this effort is to collect and clean Glot500-c, a corpus that covers these 511 languages and allows us to train Glot500-m. We evaluate Glot500-m on five diverse tasks across these languages. We observe large improvements for both high-resource and low-resource languages compared to an XLM-R baseline. Our analysis shows that no single factor explains the quality of multilingual LLM representations. Rather, a combination of factors determines quality including corpus size, script, “help” from related languages and the total capacity of the model. Our work addresses an important goal of NLP research: we should notlimit NLP to a small fraction of the world’s languages and instead strive to support as many languages as possible to bring the benefits of NLP technology to all languages and cultures. Code, data and models are available at https://github.com/cisnlp/Glot500

Chronic Kidney Disease Increases Atrial Fibrillation Inducibility: Involvement of Inflammation, Atrial Fibrosis, and Connexins

Chronic kidney disease (CKD) causes atrial structural remodeling and subsequently increases the incidence of atrial fibrillation (AF). Atrial connexins and inflammatory responses may be involved in this remodeling process. In this study, nephrectomy was used to produce the CKD rat model. Three months post-nephrectomy, cardiac structure, function and AF vulnerability were quantified using echocardiography and electrophysiology methods. The left atrial tissue was tested for quantification of fibrosis and inflammation, and for the distribution and expression of connexin (Cx) 40 and Cx43. An echocardiography showed that CKD resulted in the left atrial enlargement and left ventricular hypertrophy, but had no functional changes. CKD caused a significant increase in the AF inducible rate (91.11% in CKD group vs. 6.67% in sham group, P < 0.001) and the AF duration [107 (0–770) s in CKD vs. 0 (0–70) s in sham, P < 0.001] with prolonged P-wave duration. CKD induced severe interstitial fibrosis, activated the transforming growth factor-β1/Smad2/3 pathway with a massive extracellular matrix deposition of collagen type I and α-smooth muscle actin, and matured the NLR (nucleotide-binding domain leucine-rich repeat-containing receptor) pyrin domain-containing protein 3 (NLRP3) inflammasome with an inflammatory cascade response. CKD resulted in an increase in non-phosphorylated-Cx43, a decrease in Cx40 and phosphorylated-Cx43, and lateralized the distribution of Cx40 and Cx43 proteins with upregulations of Rac-1, connective tissue growth factor and N-cadherin. These findings implicate the transforming growth factor-β1/Smad2/3, the NLRP3 inflammasome and the connexins as potential mediators of increased AF vulnerability in CKD

An ancestral NB-LRR with duplicated 3'UTRs confers stripe rust resistance in wheat and barley.

Wheat stripe rust, caused by Puccinia striiformis f. sp. tritici (Pst), is a global threat to wheat production. Aegilops tauschii, one of the wheat progenitors, carries the YrAS2388 locus for resistance to Pst on chromosome 4DS. We reveal that YrAS2388 encodes a typical nucleotide oligomerization domain-like receptor (NLR). The Pst-resistant allele YrAS2388R has duplicated 3' untranslated regions and is characterized by alternative splicing in the nucleotide-binding domain. Mutation of the YrAS2388R allele disrupts its resistance to Pst in synthetic hexaploid wheat; transgenic plants with YrAS2388R show resistance to eleven Pst races in common wheat and one race of P. striiformis f. sp. hordei in barley. The YrAS2388R allele occurs only in Ae. tauschii and the Ae. tauschii-derived synthetic wheat; it is absent in 100% (n = 461) of common wheat lines tested. The cloning of YrAS2388R will facilitate breeding for stripe rust resistance in wheat and other Triticeae species