Salvia miltiorrhiza suppresses cardiomyocyte ferroptosis after myocardial infarction by activating Nrf2 signaling.

ETHNOPHARMACOLOGICAL RELEVANCE: Ferroptosis, a recently identified non-apoptotic form of cell death reliant on iron, is distinguished by an escalation in lipid reactive oxygen species (ROS) that are iron-dependent. This phenomenon has a strong correlation with irregularities in iron metabolism and lipid peroxidation. Salvia miltiorrhiza Bunge (DS), a medicinal herb frequently utilized in China, is highly esteemed for its therapeutic effectiveness in enhancing blood circulation and ameliorating blood stasis, particularly during the treatment of cardiovascular diseases (CVDs). Numerous pharmacological studies have identified that DS manifests antioxidative stress effects as well as inhibits lipid peroxidation. However, ambiguity persists regarding the potential of DS to impede ferroptosis in cardiomyocytes and subsequently improve myocardial damage post-myocardial infarction (MI). AIM OF THE STUDY: The present work focused on investigating whether DS could be used to prevent the ferroptosis of cardiomyocytes and improve post-MI myocardial damage. MATERIALS AND METHODS: In vivo experiments: Through ligation of the left anterior descending coronary artery, we constructed both a wild-type (WT) and NF-E2 p45-related factor 2 knockout (Nrf2-/-) mouse model of MI. Effects of DS and ferrostatin-1 (Fer-1) on post-MI cardiomyocyte ferroptosis were examined through detecting ferroptosis and myocardial damage-related indicators as well as Nrf2 signaling-associated protein levels. In vitro experiments: Erastin was used for stimulating H9C2 cardiomyocytes to construct an in vitro ferroptosis cardiomyocyte model. Effects of DS and Fer-1 on cardiomyocyte ferroptosis were determined based on ferroptosis-related indicators and Nrf2 signaling-associated protein levels. Additionally, inhibitor and activator of Nrf2 were used for confirming the impact of Nrf2 signaling on DS's effect on cardiomyocyte ferroptosis. RESULTS: In vivo: In comparison to the model group, DS suppressed ferroptosis in cardiomyocytes post-MI and ameliorated myocardial damage by inducing Nrf2 signaling-related proteins (Nrf2, xCT, GPX4), diminishing tissue ferrous iron and malondialdehyde (MDA) content. Additionally, it enhanced glutathione (GSH) levels and total superoxide dismutase (SOD) activity, effects that are aligned with those of Fer-1. Moreover, the effect of DS on alleviating cardiomyocyte ferroptosis after MI could be partly inhibited through Nrf2 knockdown. In vitro: Compared with the erastin group, DS inhibited cardiomyocyte ferroptosis by promoting the expression of Nrf2 signaling-related proteins, reducing ferrous iron, ROS, and MDA levels, but increasing GSH content and SOD activity, consistent with the effect of Fer-1. Additionally, Nrf2 inhibition increased erastin-mediated ferroptosis of cardiomyocytes through decreasing Nrf2 signaling-related protein expressions. Co-treatment with DS and Nrf2 activator failed to further enhance the anti-ferroptosis effect of DS. CONCLUSION: MI is accompanied by cardiomyocyte ferroptosis, whose underlying mechanism is probably associated with Nrf2 signaling inhibition. DS possibly suppresses ferroptosis of cardiomyocytes and improves myocardial damage after MI through activating Nrf2 signaling.

Discovery of novel ocotillol derivatives modulating glucocorticoid receptor/NF-κB signaling for the treatment of sepsis.

Glucocorticoids (GCs) have been used in the treatment of sepsis because of their potent anti-inflammatory effects. However, their clinical efficacy against sepsis remains controversial because of glucocorticoid receptor (GR) downregulation and side effects. Herein, we designed and synthesized 30 ocotillol derivatives and evaluated their anti-inflammatory activities. Ocotillol 24(R/S) differential isomers were stereoselective in their pharmacological action. Specifically, 24(S) derivatives had better anti-inflammatory activity than their corresponding 24(R) derivatives. Compound 20 most effectively inhibited NO release (85.97% reduction), and it exerted dose-dependent inhibitory effects on interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) levels. Mechanistic studies revealed that compound 20 reduces the degradation of GR mRNA and GR protein. Meanwhile, compound 20 inhibited the activation of nuclear factor-κB (NF-κB) signaling, thereby inhibiting the nuclear translocation of p65 and attenuating the inflammatory response. In vivo studies revealed that compound 20 attenuated hepatic, pulmonary, and renal pathology damage in mice with sepsis and suppressed the production of inflammatory mediators. These results indicated that compound 20 is a promising lead compound for designing and developing anti-sepsis drugs.

Multifaceted Characterization for the Hepatic Clearance of Graphene Oxide and Size-Related Hepatic Toxicity.

Understanding the final fate of nanomaterials (NMs) in the liver is crucial for their safer application. As a representative two-dimensional (2D) soft nanomaterial, graphene oxide (GO) has shown to have high potential for applications in the biomedical field, including in biosensing, drug delivery, tissue engineering, therapeutics, etc. GO has been shown to accumulate in the liver after entering the body, and thus, understanding the GO-liver interaction will facilitate the development of safer bio-applications. In this study, the hepatic clearance of two types of PEGylated GOs with different lateral sizes (s-GOs: ~70 nm and l-GOs: ~300 nm) was carefully investigated. We found that GO sheets across the hepatic sinusoidal endothelium, which then may be taken up by the hepatocytes via the Disse space. The hepatocytes may degrade GO into dot-like particles, which may be excreted via the hepatobiliary route. In combination with ICP-MS, LA-ICP-MS, and synchrotron radiation FTIR techniques, we found that more s-GO sheets in the liver were prone to be cleared via hepatobiliary excretion than l-GO sheets. A Raman imaging analysis of ID/IG ratios further indicated that both s-GO and l-GO generated more defects in the liver. The liver microsomes may contribute to GO biotransformation into O-containing functional groups, which plays an important role in GO degradation and excretion. In particular, more small-sized GO sheets in the liver were more likely to be cleared via hepatobiliary excretion than l-GO sheets, and a greater clearance of s-GO will mitigate their hepatotoxicity. These results provide a better understanding of the hepatic clearance of soft NMs, which is important in the safer-by-design of GO.

Exploration of the Polymorphism Distribution of Bovine HMGA2 Gene in Worldwide Breeds and Its Associations with Ovarian Traits.

The high-mobility group AT-hook 2(HMGA2) gene has been widely studied in the context of cancer and animal growth. However, recently, several studies have uncovered its critical role in cell proliferation. A genome-wide association study (GWAS) further suggests that the HMGA2 gene is a candidate gene in fertility, indicating its connection not only to growth traits but also to reproduction, specifically ovarian traits. Thus, this study aimed to analyze the distribution of the HMGA2 gene in 54 bovine breeds worldwide, identify important short fragment variants (indels), and investigate the relationship between HMGA2 and ovarian development. The dataset included genotypic information from a bovine population of 634 individuals (n = 634). After genotyping and analyzing four selected loci, we found that one out of four loci, rs133750033 (P4-D22-bp), was polymorphic. Our results also reveal that this indel of HMGA2 is significantly associated with certain ovarian traits (p < 0.05). Specifically, it has connection with ovarian length (p = 0.004) and ovarian height (p = 0.026) during diestrus. Additionally, we discovered a higher expression of the HMGA2 gene in Asian cattle breeds. In summary, this study suggests that HMGA2 has the potential to serve as an animal fertility testing marker gene. Moreover, these findings contribute to a more promising outlook for the bovine industry.

Low molecular weight acids and OATP1B mediated hepatic clearance: In vitro and in vivo evaluation using novel hypoxia-inducible factor prolyl hydroxylase inhibitors (Dustats).

Organic anion transporting polypeptide (OATP1B) plays a key role in the hepatic clearance of a majority of high molecular weight (MW) acids and zwitterions. Here, we evaluated the role of OATP1B-mediated uptake in the clearance of novel hypoxia-inducible factor prolyl hydroxylase inhibitors ("Dustats"), which are typically low MW (300-400 daltons) aliphatic carboxylic acids. Five acid dustats, namely daprodustat, desidustat, enarodustat, roxadustat and vadadustat, showed specific transport by OATP1B1/1B3 in transporter-transfected HEK293 cells. Neutral compound, molidustat, was not a substrate to OATP1B1/1B3. None of the dustats showed transport by other hepatic uptake transporters, including NTCP, OAT2 and OAT7. In the primary human hepatocytes, uptake of all acids was significantly reduced by rifampin (OATP1B inhibitor); with an estimated fraction transported by OATP1B (ft ,OATP1B) of up to >80% (daprodustat). Molidustat uptake was minimally inhibited by rifampin; and low permeability acids (desidustat and enarodustat) also showed biliary efflux in sandwich culture human hepatocytes. In vivo, intravenous pharmacokinetics of all 5 acids was significantly altered by a single-dose rifampin (30 mg/kg) in Cynomolgus monkey. Hepatic clearance (non-renal) was about 4-fold (vadadustat) to >11-fod (daprodustat and roxadustat) higher in control group compared to rifampin-treated subjects. In vivo ft ,OATP1B was estimated to be ~70-90%. In the case of molidustat, rifampin had a minimal effect on overall clearance. Rifampin also considerably reduced volume of distribution of daprodustat and roxadustat. Overall, OATP1B significantly contribute to the hepatic clearance and pharmacokinetics of several dustats, which are low MW carboxylic acids. OATP1B activity should therefore by evaluated in this property space. Significance Statement Our in vitro and in vivo results suggest that OATP1B-mediated hepatic uptake play a significant role in the pharmacokinetics of low MW acidic dustats, which are being developed or approved for the treatment of anemia in chronic kidney disease. Significant active uptake mechanisms are not apparent for the neutral compound, molidustat. Characterization of uptake mechanisms is therefore important in predicting human pharmacokinetics and evaluating drug-drug interactions for low MW acids.

Mechanistic Determinants of Daprodustat Drug-Drug Interactions and Pharmacokinetics in Hepatic Dysfunction and Chronic Kidney Disease: Significance of OATP1B-CYP2C8 Interplay.

Daprodustat is the first oral hypoxia-inducible factor prolyl hydroxylase inhibitor approved recently for the treatment of anemia caused by chronic kidney disease (CKD) in adults receiving dialysis. We evaluated the role of organic anion transporting polypeptide (OATP)1B-mediated hepatic uptake transport in the pharmacokinetics (PKs) of daprodustat using in vitro and in vivo studies, and physiologically-based PK (PBPK) modeling of its drug-drug interactions (DDIs) with inhibitor drugs. In vitro, daprodustat showed specific transport by OATP1B1/1B3 in the transfected cell systems and primary human and monkey hepatocytes. A single-dose oral rifampin (OATP1B inhibitor) reduced daprodustat intravenous clearance by a notable 9.9 ± 1.2-fold (P < 0.05) in cynomolgus monkeys. Correspondingly, volume of distribution at steady-state was also reduced by 5.0 ± 1.1-fold, whereas the half-life change was minimal (1.5-fold), corroborating daprodustat hepatic uptake inhibition by rifampin. A PBPK model accounting for OATP1B-CYP2C8 interplay was developed, which well described daprodustat PK and DDIs with gemfibrozil (CYP2C8 and OATP1B inhibitor) and trimethoprim (weak CYP2C8 inhibitor) within 25% error of the observed data in healthy subjects. About 18-fold increase in daprodustat area under the curve (AUC) following gemfibrozil treatment was found to be associated with strong CYP2C8 inhibition and moderate OATP1B inhibition. Moreover, PK modulation in hepatic dysfunction and subjects with CKD, in comparison to healthy control, was well-captured by the model. CYP2C8 and/or OATP1B inhibitor drugs (e.g., gemfibrozil, clopidogrel, rifampin, and cyclosporine) were predicted to perpetrate moderate-to-strong DDIs in healthy subjects, as well as, in target CKD population. Daprodustat can be used as a sensitive CYP2C8 index substrate in the absence of OATP1B modulation.

Neuro-inspired optical sensor array for high-accuracy static image recognition and dynamic trace extraction.

Neuro-inspired vision systems hold great promise to address the growing demands of mass data processing for edge computing, a distributed framework that brings computation and data storage closer to the sources of data. In addition to the capability of static image sensing and processing, the hardware implementation of a neuro-inspired vision system also requires the fulfilment of detecting and recognizing moving targets. Here, we demonstrated a neuro-inspired optical sensor based on two-dimensional NbS2/MoS2 hybrid films, which featured remarkable photo-induced conductance plasticity and low electrical energy consumption. A neuro-inspired optical sensor array with 10 × 10 NbS2/MoS2 phototransistors enabled highly integrated functions of sensing, memory, and contrast enhancement capabilities for static images, which benefits convolutional neural network (CNN) with a high image recognition accuracy. More importantly, in-sensor trajectory registration of moving light spots was experimentally implemented such that the post-processing could yield a high restoration accuracy. Our neuro-inspired optical sensor array could provide a fascinating platform for the implementation of high-performance artificial vision systems.

Detection distribution of CNVs of SNX29 in three goat breeds and their associations with growth traits.

As a member of the SNX family, the goat sorting nexin 29 (SNX29) is initially identified as a myogenesis gene. Therefore, this study aimed to examine the polymorphism in the SNX29 gene and its association with growth traits. In this study, we used an online platform to predict the structures of the SNX29 protein and used quantitative real-time PCR to detect potential copy number variation (CNV) in Shaanbei white cashmere (SBWC) goats (n = 541), Guizhou black (GB) goats (n = 48), and Nubian (NB) goats (n = 39). The results showed that goat SNX29 protein belonged to non-secretory protein. Then, five CNVs were detected, and their association with growth traits was analyzed. In SBWC goats, CNV1, CNV3, CNV4, and CNV5 were associated with chest width and body length (P < 0.05). Among them, the CNV1 individuals with gain and loss genotypes were superior to those individuals with a median genotype, but CNV4 and CNV5 of individuals with the median genotype were superior to those with the loss and gain genotypes. In addition, individuals with the gain genotype had superior growth traits in CNV3. In brief, this study suggests that the CNV of SNX29 can be used as a molecular marker in goat breeding.

Advances in the anti-tumor potential of hederagenin and its analogs.

Hederagenin is a pentacyclic triterpenoid that is widely distributed as the main pharmaceutical ingredient in various medicinal plants. Similarly as other pentacyclic triterpenoids, hederagenin has various pharmacological effects such as anti-tumor, anti-inflammatory, anti-depressant, and anti-viral activities. In particular, the anti-tumor activity of hederagenin indicates its potential for development into highly effective chemotherapeutic agents. Studies revealed that hederagenin effectively suppresses the growth of various tumor cell lines in vitro and interacts with several molecular targets that play essential roles in various cellular signaling pathways. The compound suppresses transformation, inhibits proliferation, and induces apoptosis in tumor cells. In this review, we highlight research progress on the source, pharmacokinetics, pharmacological activity, and mechanism of action of hederagenin and the anti-tumor activity of its analogs by integrating and analyzing relevant domestic and international studies and providing a basis for their further development and application.

Recommendations on screening mammography in patients with ventriculoperitoneal shunts and deep brain stimulation.

Insertion of ventriculoperitoneal (VP) shunt and deep brain stimulation (DBS) are common neurosurgical procedures. Concerns have been raised regarding the safety of mammography in this patient cohort due to the risk of damaging the VP shunt tubing or DBS implantable pulse generator, and the degradation in mammography image quality secondary to the implanted devices. Based on a review of the current literature, the authors propose that mammography is safe in patients with VP shunts and DBS, and should be performed routinely as a part of population screening.

Characterization of Bile Acid Sulfate Conjugates as Substrates of Human Organic Anion Transporting Polypeptides.

Drug interactions involving the inhibition of hepatic organic anion transporting polypeptides (OATPs) 1B1 and OATP1B3 are considered important. Therefore, we sought to study various sulfated bile acids (BA-S) as potential clinical OATP1B1/3 biomarkers. It was determined that BA-S [e.g., glycochenodeoxycholic acid 3-O-sulfate (GCDCA-S) and glycodeoxycholic acid 3-O-sulfate (GDCA-S)] are substrates of OATP1B1, OATP1B3, and sodium-dependent taurocholic acid cotransporting polypeptide (NTCP) transfected into human embryonic kidney 293 cells, with minimal uptake evident for other solute carriers (SLCs) like OATP2B1, organic anion transporter 2, and organic cation transporter 1. It was also shown that BA-S uptake by plated human hepatocytes (PHH) was inhibited (≥96%) by a pan-SLC inhibitor (rifamycin SV), and there was greater inhibition (≥77% versus ≤12%) with rifampicin (OATP1B1/3-selective inhibitor) than a hepatitis B virus myristoylated-preS1 peptide (NTCP-selective inhibitor). Estrone 3-sulfate was also used as an OATP1B1-selective inhibitor. In this instance, greater inhibition was observed with GDCA-S (76%) than GCDCA-S (52%). The study was expanded to encompass the measurement of GCDCA-S and GDCA-S in plasma of SLCO1B1 genotyped subjects. The geometric mean GDCA-S concentration was 2.6-fold (90% confidence interval 1.6, 4.3; P = 2.1 × 10-4) and 1.3-fold (1.1, 1.7; P = 0.001) higher in individuals homozygous and heterozygous for the SLCO1B1 c.521T > C loss-of-function allele, respectively. For GCDCA-S, no significant difference was noted [1.2-fold (0.8, 1.7; P = 0.384) and 0.9-fold (0.8, 1.1; P = 0.190), respectively]. This supported the in vitro data indicating that GDCA-S is a more OATP1B1-selective substrate (versus GCDCA-S). It is concluded that GCDCA-S and GDCA-S are viable plasma-based OATP1B1/3 biomarkers, but they are both less OATP1B1-selective when compared to their corresponding 3-O-glucuronides (GCDCA-3G and GDCA-3G). Additional studies are needed to determine their utility versus more established biomarkers, such as coproporphyrin I, for assessing inhibitors with different OATP1B1 (versus OATP1B3) inhibition signatures.

A new model based on gamma-glutamyl transpeptidase to lymphocyte ratio and systemic immune-inflammation index can effectively predict the recurrence of hepatocellular carcinoma after liver transplantation.

Background: Liver transplantation (LT) is one of the most effective treatment modalities for hepatocellular carcinoma (HCC), but patients with HCC recurrence after LT always have poor prognosis. This study aimed to evaluate the predictive value of the gamma-glutamyl transpeptidase-to-lymphocyte ratio (GLR) and systemic immune-inflammation index (SII) in terms of HCC recurrence after LT, based on which we developed a more effective predictive model. Methods: The clinical data of 325 HCC patients who had undergone LT were collected and analyzed retrospectively. The patients were randomly divided into a development cohort (n = 215) and a validation cohort (n = 110). Cox regression analysis was used to screen the independent risk factors affecting postoperative recurrence in the development cohort, and a predictive model was established based on the results of the multivariate analysis. The predictive values of GLR, SII and the model were evaluated by receiver operating characteristic (ROC) curve analysis, which determined the cut-off value for indicating patients' risk levels. The Kaplan-Meier survival analysis and the competing-risk regression analysis were used to evaluate the predictive performance of the model, and the effectiveness of the model was verified further in the validation cohort. Results: The recurrence-free survival of HCC patients after LT with high GLR and SII was significantly worse than that of patients with low GLR and SII (P<0.001). Multivariate Cox regression analysis identified GLR (HR:3.405; 95%CI:1.954-5.936; P<0.001), SII (HR: 2.285; 95%CI: 1.304-4.003; P=0.004), tumor number (HR:2.368; 95%CI:1.305-4.298; P=0.005), maximum tumor diameter (HR:1.906; 95%CI:1.121-3.242; P=0.017), alpha-fetoprotein level (HR:2.492; 95%CI:1.418-4.380; P=0.002) as independent risk factors for HCC recurrence after LT. The predictive model based on these risk factors had a good predictive performance in both the development and validation cohorts (area under the ROC curve=0.800, 0.791, respectively), and the performance of the new model was significantly better than that of single GLR and SII calculations (P<0.001). Survival analysis and competing-risk regression analysis showed that the predictive model could distinguish patients with varying levels of recurrence risk in both the development and validation cohorts. Conclusions: The GLR and SII are effective indicators for evaluating HCC recurrence after LT. The predictive model based on these indicators can accurately predict HCC recurrence after LT and is expected to guide preoperative patient selection and postoperative follow-up.

3D-imaging and quantitative assessment for size-related penetration of HfO2 nanoparticles in breast cancer tumor by synchrotron radiation microcomputed tomography.

The development of quantitative analytical methods to assess the heterogeneous distribution and penetration of nanodrugs in solid tumors is of great importance for anticancer nanomedicine. Herein, Expectation-Maximization (EM) iterate algorithm and threshold segmentation methods were used to visualize and quantify the spatial distribution patterns, penetration depth and diffusion features of two-sized hafnium oxide nanoparticles (s-HfO2 NPs in 2 nm and l-HfO2 NPs in 50 nm sizes) in mouse models of breast cancer using synchrotron radiation micro-computed tomography (SR-µCT) imaging technique. The three-dimensional (3D) SR-µCT images were reconstructed based on the EM iterate algorithm thus clearly displayed the size-related penetration and distribution within the tumors after intra-tumoral injection of HfO2 NPs and X-ray irradiation treatment. The obtained 3D animations clearly show that a considerable amount of s-HfO2 and l-HfO2 NPs diffused into tumor tissues at 2 h post-injection and displayed the obvious increase in the tumor penetration and distribution area within the tumors at day 7 after combination with low-dose X-ray irradiation treatment. A thresholding segmentation for 3D SR-µCT image was developed to assess the penetration depth and quantity of HfO2 NPs along the injection sites in tumors. The developed 3D-imaging techniques revealed that the s-HfO2 NPs presented more homogeneous distribution pattern, diffused more quickly and penetrated more deeply within tumor tissues than the l-HfO2 NPs did. Whereas, the low-dose X-ray irradiation treatment greatly enhanced the wide distribution and deep penetration of both s-HfO2 and l-HfO2 NPs. This developed method may provide quantitative distribution and penetration information for the X-ray sensitive high-Z metal nanodrugs in the cancer imaging and therapy.

Bi-Functionalized Transferrin@MoS2-PEG Nanosheets for Improving Cellular Uptake in HepG2 Cells.

Pre-coating with a protein corona on the surface of nanomaterials (NMs) is an important strategy for reducing non-specific serum protein absorption while maintaining targeting specificity. Here, we present lipoic acid-terminated polyethylene glycol and transferrin bi-functionalized MoS2 nanosheets (Tf@MoS2-PEG NSs) as a feasible approach to enhance cellular uptake. Tf@MoS2-PEG NSs can maintain good dispersion stability in cell culture medium and effectively protect MoS2 NSs from oxidation in ambient aqueous conditions. Competitive adsorption experiments indicate that transferrin was more prone to bind MoS2 NSs than bovine serum albumin (BSA). It is noteworthy that single HepG2 cell uptake of Tf@MoS2-PEG presented a heterogeneous distribution pattern, and the cellular uptake amount spanned a broader range (from 0.4 fg to 2.4 fg). Comparatively, the intracellular Mo masses in HepG2 cells treated with BSA@MoS2-PEG and MoS2-PEG showed narrower distribution, indicating homogeneous uptake in the single HepG2 cells. Over 5% of HepG2 cells presented uptake of the Tf@MoS2-PEG over 1.2 fg of Mo, about three-fold that of BSA@MoS2-PEG (0.4 fg of Mo). Overall, this work suggests that Tf coating enhances the cellular uptake of MoS2 NSs and is a promising strategy for improving the intracellular uptake efficiency of cancer cells.

Boosting thermoelectric performance of HfSe2 monolayer by selectivity chemical adsorption.

In this work, a strategy to boosting thermoelectric (TE) performance of 2D materials is explored. We find that, appropriate chemical adsorption of atoms can effectively increase the TE performance of HfSe2 monolayer. Our results show that the adsorption of Ni atom on HfSe2 monolayer (Ni-HfSe2) can improve the optimal power factor PF and ZT at 300 K, increased by more than ∼67% and ∼340%, respectively. The PF and ZT of Ni-HfSe2 at 300 K can reach 85.06 mW m-1 K-2 and 3.09, respectively. The detailed study reveal that the adsorption of Ni atom can induce additional conductional channels of electrons, enhance the coupling of acoustic-optical phonons and the phonon anharmonicity, resulting in an obvious increment of electrical conductivity (increased by more than ∼89%) in n-type doped system and an ultralow phonon thermal conductivity (1.17 W/mK at 300 K). The high electrical conductivity and ultralow phonon thermal conductivity results in the significant increments of PF and ZT. Our study also shows that, Ni-HfSe2 is a thermal, dynamic and mechanical stable structure, which can be employed in TE application. Our research indicates that selectivity chemical adsorption is a promising way to increase TE performance of 2D materials.

Strain Tunable Thermoelectric Material: Janus ZrSSe Monolayer.

Thermoelectric (TE) performance of the Janus ZrSSe monolayer under biaxial strain is systematically explored by the first-principles approach and Boltzmann transport theory. Our results show that the Janus ZrSSe monolayer has excellent chemical, dynamical, thermal, and mechanical stabilities, which provide a reliable platform for strain tuning. The electronic structure and TE transport parameters of the Janus ZrSSe monolayer can be obviously tuned by biaxial strain. Under 2% tensile strain, the optimal power factor PF of the n-type-doped Janus ZrSSe monolayer reaches 46.36 m W m-1 K-2 at 300 K. This value is higher than that of the most classical TE materials. Under 6% tensile strain, the maximum ZT values for the p-type- and n-type-doped Janus ZrSSe monolayers are 4.41 and 4.88, respectively, which are about 3.83 and 1.49 times the results of no strain, respectively. Such high TE performance can be attributed to high band degeneracy and short phonon relaxation time under strain, causing simultaneous increase of the Seebeck coefficient and suppression of the phonon thermal transport. Present work demonstrates that the Janus ZrSSe monolayer is a promising candidate as a strain-tunable TE material and stimulates further experimental synthesis.

A 14-bp deletion in bovine EPAS1 gene is associated with carcass traits.

EPAS1 (Endothelial PAS Domain Protein 1) gene is well-known for its function in plateau hypoxia adaptability. It encodes HIF-2α, which involved in the induction of genes regulated by oxygen and then affects multiple physiological processes such as angiogenesis and energy metabolism. All of these indicate it may affect the development of animals. In this study, a 14-bp deletion in EPAS1 gene was uncovered in Shandong black cattle population (n = 502). Two genotypes (II and ID) were found and the frequency of the homozygous II genotype is higher than the heterozygous ID genotype. This population is consisted with HWE (p > 0.05). And more importantly, the 14-bp deletion was associated with outside flat (p = 0.003), brisket (p = 0.001), and knuckle (p = 0.032). These findings suggested that the 14-bp deletion is significantly associated with carcass traits, which could be served as a molecular marker applied to cow breeding.

Survey of the relationship between polymorphisms within the BMPR1B gene and sheep reproductive traits.

The BMPRIB gene is one of the main genes that can be used as a molecular genetic marker for the early selection of highly productive ewes. It is well-documented that the p.Q249R (g.746A > G) is the first mutation in the kinase domain of the BMPR1B gene that is highly related to increased ovulation rate and litter size. It is likely that the presence of the p.Q249R mutation in the sheep population is one of the factors contributing to the outstanding productivity of the sheep. Moreover, in recent years, researchers have been explored other polymorphisms in the BMPR1B gene with respect to reproductive traits in sheep. Therefore, we carried out the current study to evaluate the association between polymorphisms in this gene and sheep litter size from all appropriate studies. As a result, among 41 polymorphisms in the ovine BMPRIB gene, eight variants, including p.Q249R (g.746A > G), g.29362047T > C, g.29427689G > A, BMPR1B-2 (ss:1960972599), g.29382337G > A, g.29382340G > A, rs1092293287 (10 bp insertion/deletion) and g.29380965A > G were found to be associated with litter size in sheep. This systematic analysis presents the most current data evidence for BMPRIB polymorphisms, highlighting the need for further large-scale studies to determine more important variants.

Investigation of Genetic Effects of Nucleotide Variants Within the Goat PRNT Gene on Growth Performance.

Our previous study has firstly pointed that three nucleotide variants (g.-11C > T, g.117A > G, and g.149C > T) of the goat PRNT gene can significantly influence litter size. Given litter size is positively correlated with growth performance, we consider whether the PRNT gene also acts on the growth performance in goats. In this work, a correlation analysis among different litter size types and growth traits of Shaanbei white cashmere (SBWC) goats was performed, and results showed that a positive correlation did exist in our detected population (P < 0.01). Then, the association among different genotypes of three variations and goat growth performance was measured. Our results pointed to g.117A > G being significantly associated with the cannon circumference (P = 4.60E-05) while no significant effect was found between another two SNPs and growth traits after the Bonferroni's correction (P*n < 0.05). Together, this is the first report about the influence of the PRNT gene on the growth of goat and g.117A > G can be regarded as a possible DNA marker applying for MAS breeding.

Design and synthesis of hederagenin derivatives modulating STING/NF-κB signaling for the relief of acute liver injury in septic mice.

Systemic inflammatory responses often result in sepsis and inhibition of inflammation is one strategy for sepsis treatment. In this study, we designed and synthesized 32 novel hederagenin (HD) derivatives with modifications at the A-ring, C-28, and C-23 positions and screened their anti-inflammatory activities in vitro, finding multiple compounds with potential anti-inflammatory activity. Of these, compound 1 was the most effective and was used for subsequent investigations into its mechanism of action and in vivo activity. In vivo assessments of anti-inflammatory activity showed that compound 1 reduced inflammation in a mouse model of sepsis with acute liver injury caused by lipopolysaccharide (LPS). Compound 1 also inhibited STING, p-IRF3, p-TBK1, p-p65, and p-IκB proteins in cGAS-STING-associated signaling. These findings indicated that compound 1 reduced inflammation through inhibition of STING expression and hence reducing activation of STING and nuclear factor-κB (NF-κB) signaling. Our work demonstrated that compound 1 is a promising lead compound for designing and developing anti-sepsis drugs.