Effects of Cadmium Stress on Tartary Buckwheat Seedlings.

Cadmium (Cd) is a naturally occurring toxic heavy metal that adversely affects plant germination, growth, and development. While the effects of Cd have been described on many crop species including rice, maize, wheat and barley, few studies are available on cadmium's effect on Tartary buckwheat which is a traditional grain in China. We examined nine genotypes and found that 30 µM of Cd reduced the root length in seedlings by between 4 and 44% and decreased the total biomass by 7 to 31%, compared with Cd-free controls. We identified a significant genotypic variation in sensitivity to Cd stress. Cd treatment decreased the total root length and the emergence and growth of lateral roots, and these changes were significantly greater in the Cd-sensitive genotypes than in tolerant genotypes. Cd resulted in greater wilting and discoloration in sensitive genotypes than in tolerant genotypes and caused more damage to the structure of root and leaf cells. Cd accumulated in the roots and shoots, but the concentrations in the sensitive genotypes were significantly greater than in the more tolerant genotypes. Cd treatment affected nutrient uptake, and the changes in the sensitive genotypes were greater than those in the tolerant genotypes, which could maintain their concentrations closer to the control levels. The induction of SOD, POD, and CAT activities in the roots and shoots was significantly greater in the tolerant genotypes than in the sensitive genotypes. We demonstrated that Cd stress reduced root and shoot growth, decreased plant biomass, disrupted nutrient uptake, altered cell structure, and managed Cd-induced oxidative stress differently in the sensitive and tolerant genotypes of Tartary buckwheat.

Discovery of HC-7366: An Orally Bioavailable and Efficacious GCN2 Kinase Activator.

A series of activators of GCN2 (general control nonderepressible 2) kinase have been developed, leading to HC-7366, which has entered the clinic as an antitumor therapy. Optimization resulted in improved permeability compared to that of the original indazole hinge binding scaffold, while maintaining potency at GCN2 and selectivity over PERK (protein kinase RNA-like endoplasmic reticulum kinase). The improved ADME properties of this series led to robust in vivo compound exposure in both rats and mice, allowing HC-7366 to be dosed in xenograft models, demonstrating that activation of the GCN2 pathway by this compound leads to tumor growth inhibition.

Efficacy and safety of sacubitril/valsartan after six months in patients with heart failure with reduced ejection fraction and asymptomatic hypotension / 老年心脏病学杂志（英文版）

BACKGROUND@#It is not clear whether sacubitril/valsartan is beneficial for patients with heart failure (HF) with reduced ejection fraction (HFrEF) and low systolic blood pressure (SBP). This study aimed to investigate the efficacy and tolerability of sacubitril/valsartan in HFrEF patients with SBP < 100 mmHg.@*METHODS & RESULTS@#An observational study was conducted on 117 patients, 40.2% of whom had SBP < 100 mmHg without symptomatic hypotension, and 59.8% of whom had SBP ≥ 100 mmHg in an optimized HF follow-up management system. At the 6-month follow-up, 52.4% of patients with SBP < 100 mmHg and 70.0% of those with SBP ≥ 100 mmHg successfully reached the target dosages of sacubitril/valsartan. A reduction in the concentration of N-terminal pro-B-type natriuretic peptide was similar between patients with SBP < 100 mmHg and SBP ≥ 100 mmHg (1627.5 pg/mL and 1340.1 pg/mL, respectively; P = 0.75). The effect of sacubitril/valsartan on left ventricular ejection fraction was observed in both SBP categories, with a 10.8% increase in patients with SBP < 100 mmHg (P < 0.001) and a 14.0% increase in patients with SBP ≥ 100 mmHg (P < 0.001). The effects of sacubitril/valsartan on SBP were statistically significant and inverse across both SBP categories (P = 0.001), with an increase of 7.5 mmHg in patients with SBP < 100 mmHg and a decrease of 11.5 mmHg in patients with SBP ≥ 100 mmHg. No statistically significant differences were observed between the two groups in terms of the occurrence of symptomatic hypotension, deteriorating renal function, hyperkalemia, angioedema, or stroke.@*CONCLUSIONS@#Within an optimized HF follow-up management system, sacubitril/valsartan exhibited excellent tolerability and prompted left ventricular reverse remodeling in patients with HFrEF who presented asymptomatic hypotension.

Study on the construction and quality evaluation of courses for ideological and political education in the course of oral histology and pathology / 中华口腔医学杂志

To give full play to the important role of courses for ideological and political education in moral cultivation, teaching group in the course of oral histology and pathology in Zhejiang University systematically studied the teaching model of which ideological and political education integrated into the course of oral histology and pathology, and put forward a quality evaluation index system of the course. This paper emphatically introduces the general framework of the course, as well as the experience and practices in the aspects of resource mining, teaching design, curriculum evaluation, etc. The quality of the course was evaluated by using the system, which showed that the grade of the course was AAA (excellent) and 95.5% (275/288) students agreed to integrate ideological and political content into the course. The teaching group believes that the integration of the ideological and political content in the course reflects the complementary effect of "teaching" and "educating", and the ideological and political quality as well as the professional level of the teachers are the primary factor to determine the quality of the course. This paper aims at providing a reliable reference for promoting the construction of courses for ideological and political education in the area of oral medical education.

Efficacy and safety of sacubitril/valsartan after six months in patients with heart failure with reduced ejection fraction and asymptomatic hypotension.

BACKGROUND: It is not clear whether sacubitril/valsartan is beneficial for patients with heart failure (HF) with reduced ejection fraction (HFrEF) and low systolic blood pressure (SBP). This study aimed to investigate the efficacy and tolerability of sacubitril/valsartan in HFrEF patients with SBP < 100 mmHg. METHODS & RESULTS: An observational study was conducted on 117 patients, 40.2% of whom had SBP < 100 mmHg without symptomatic hypotension, and 59.8% of whom had SBP ≥ 100 mmHg in an optimized HF follow-up management system. At the 6-month follow-up, 52.4% of patients with SBP < 100 mmHg and 70.0% of those with SBP ≥ 100 mmHg successfully reached the target dosages of sacubitril/valsartan. A reduction in the concentration of N-terminal pro-B-type natriuretic peptide was similar between patients with SBP < 100 mmHg and SBP ≥ 100 mmHg (1627.5 pg/mL and 1340.1 pg/mL, respectively; P = 0.75). The effect of sacubitril/valsartan on left ventricular ejection fraction was observed in both SBP categories, with a 10.8% increase in patients with SBP < 100 mmHg (P < 0.001) and a 14.0% increase in patients with SBP ≥ 100 mmHg (P < 0.001). The effects of sacubitril/valsartan on SBP were statistically significant and inverse across both SBP categories (P = 0.001), with an increase of 7.5 mmHg in patients with SBP < 100 mmHg and a decrease of 11.5 mmHg in patients with SBP ≥ 100 mmHg. No statistically significant differences were observed between the two groups in terms of the occurrence of symptomatic hypotension, deteriorating renal function, hyperkalemia, angioedema, or stroke. CONCLUSIONS: Within an optimized HF follow-up management system, sacubitril/valsartan exhibited excellent tolerability and prompted left ventricular reverse remodeling in patients with HFrEF who presented asymptomatic hypotension.

Role of Interleukin-36 in inflammatory joint diseases / 浙江大学学报·医学版

Interleukin (IL)-36 is a family of cytokines that belongs to the larger IL-1 superfamily. IL-36 agonist/antagonist binds to the interleukin-36 receptor involving in physiological inflammation regulation and pathogenesis of many inflammatory diseases. In inflammatory joint diseases, the expression of IL-36 changes, and some studies have initially explored the role of IL-36 in these diseases. In psoriatic arthritis, IL-36 signal mediates plasma cell and fibroblast-like synoviocyte crosstalk presenting IL-36 agonist/antagonist imbalance. In rheumatoid arthritis, IL-36 agonists induce fibroblast-like synoviocyte to produce pro-inflammatory factors, while IL-36 antagonist deficiency leads to lesion progression. In osteoarthritis, IL-36 agonists induce chondrocytes to produce catabolic enzymes and pro-inflammatory factors. This article reviews the expression and function of IL-36 in different inflammatory joint diseases to provide a reference for revealing their pathogenic mechanisms and discovering therapeutic targets.

Optimization of a Novel Mandelamide-Derived Pyrrolopyrimidine Series of PERK Inhibitors.

The protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) is one of three endoplasmic reticulum (ER) transmembrane sensors of the unfolded protein response (UPR) responsible for regulating protein synthesis and alleviating ER stress. PERK has been implicated in tumorigenesis, cancer cell survival as well metabolic diseases such as diabetes. The structure-based design and optimization of a novel mandelamide-derived pyrrolopyrimidine series of PERK inhibitors as described herein, resulted in the identification of compound 26, a potent, selective, and orally bioavailable compound suitable for interrogating PERK pathway biology in vitro and in vivo, with pharmacokinetics suitable for once-a-day oral dosing in mice.

FtNAC31, a Tartary buckwheat NAC transcription factor, enhances salt and drought tolerance in transgenic Arabidopsis.

Tartary buckwheat [Fagopyrum tataricum (L.) Gaertn.] is a pseudocereal with strongly abiotic resistance. NACs, one of the largest plant-specific transcription factors (TFs), are involved in various stress responses. However, the characteristics and regulatory mechanisms of NAC TFs remain unclarified clearly in Tartary buckwheat (TB). In this study, it validated that salt, drought, and abscisic acid (ABA) stress significantly up-regulated the expression of NAC TF gene FtNAC31. Its coding protein has a C-terminal transactivated domain and localized in the nucleus, suggesting that FtNAC31 might play a transcriptional activation role in TB. Notably, overexpression of FtNAC31 lowered the seed germination rate upon ABA treatment and enhanced the tolerance to salt and drought stress in transgenetic Arabidopsis. Furthermore, under various stresses, the activities of superoxide dismutase (SOD), peroxidase (POD), and catalase (CAT) in FtNAC31 overexpressed lines exhibited a sharp increase trend. Meanwhile, the expression levels of several stress-associated genes including RD29A, RD29B, RD22, DREB2B, NCED3, and POD1, were dramatically upregulated in lines overexpressing FtNAC31. Altogether, overproduction of FtNAC31 could enhance the resistance to salt and drought stresses in transgenic Arabidopsis, which most likely functioned in an ABA-dependent way.

Plastome comparison and phylogenomics of Fagopyrum (Polygonaceae): insights into sequence differences between Fagopyrum and its related taxa.

BACKGROUND: Fagopyrum (Polygonaceae) is a small plant lineage comprised of more than fifteen economically and medicinally important species. However, the phylogenetic relationships of the genus are not well explored, and the characteristics of Fagopyrum chloroplast genomes (plastomes) remain poorly understood so far. It restricts the comprehension of species diversity in Fagopyrum. Therefore, a comparative plastome analysis and comprehensive phylogenomic analyses are required to reveal the taxonomic relationship among species of Fagopyrum. RESULTS: In the current study, 12 plastomes were sequenced and assembled from eight species and two varieties of Fagopyrum. In the comparative analysis and phylogenetic analysis, eight previously published plastomes of Fagopyrum were also included. A total of 49 plastomes of other genera in Polygonaceae were retrieved from GenBank and used for comparative analysis with Fagopyrum. The variation of the Fagopyrum plastomes is mainly reflected in the size and boundaries of inverted repeat/single copy (IR/SC) regions. Fagopyrum is a relatively basal taxon in the phylogenomic framework of Polygonaceae comprising a relatively smaller plastome size (158,768-159,985 bp) than another genus of Polygonaceae (158,851-170,232 bp). A few genera of Polygonaceae have nested distribution of the IR/SC boundary variations. Although most species of Fagopyrum show the same IRb/SC boundary with species of Polygonaceae, only a few species show different IRa/SC boundaries. The phylogenomic analyses of Fagopyrum supported the cymosum and urophyllum groups and resolved the systematic position of subclades within the urophyllum group. Moreover, the repeat sequence types and numbers were found different between groups of Fagopyrum. The plastome sequence identity showed significant differences between intra-group and inter-group. CONCLUSIONS: The deletions of intergenic regions cause a short length of Fagopyrum plastomes, which may be the main reason for plastome size diversity in Polygonaceae species. The phylogenomic reconstruction combined with the characteristics comparison of plastomes supports grouping within Fagopyrum. The outcome of these genome resources may facilitate the taxonomy, germplasm resources identification as well as plant breeding of Fagopyrum.

Discovery of 2-amino-3-amido-5-aryl-pyridines as highly potent, orally bioavailable, and efficacious PERK kinase inhibitors.

The protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) is one of the three endoplasmic reticulum (ER) transmembrane sensors of the unfolded protein response (UPR) that regulates protein synthesis, alleviates cellular ER stress and has been implicated in tumorigenesis and prolonged cancer cell survival. In this study, we report a series of 2-amino-3-amido-5-aryl-pyridines that we have identified as potent, selective, and orally bioavailable PERK inhibitors. Amongst the series studied herein, compound (28) a (R)-2-Amino-5-(4-(2-(3,5-difluorophenyl)-2-hydroxyacetamido)-2-ethylphenyl)-N-isopropylnicotinamide has demonstrated potent biochemical and cellular activity, robust pharmacokinetics and 70% oral bioavailability in mice. Given these data, this compound (28) was studied in the 786-O renal cell carcinoma xenograft model. We observed dose-dependent, statistically significant tumor growth inhibition, supporting the use of this tool compound in additional mechanistic studies.

Hippocampal Interneurons are Required for Trace Eyeblink Conditioning in Mice / 神经科学通报·英文版

While the hippocampus has been implicated in supporting the association among time-separated events, the underlying cellular mechanisms have not been fully clarified. Here, we combined in vivo multi-channel recording and optogenetics to investigate the activity of hippocampal interneurons in freely-moving mice performing a trace eyeblink conditioning (tEBC) task. We found that the hippocampal interneurons exhibited conditioned stimulus (CS)-evoked sustained activity, which predicted the performance of conditioned eyeblink responses (CRs) in the early acquisition of the tEBC. Consistent with this, greater proportions of hippocampal pyramidal cells showed CS-evoked decreased activity in the early acquisition of the tEBC. Moreover, optogenetic suppression of the sustained activity in hippocampal interneurons severely impaired acquisition of the tEBC. In contrast, suppression of the sustained activity of hippocampal interneurons had no effect on the performance of well-learned CRs. Our findings highlight the role of hippocampal interneurons in the tEBC, and point to a potential cellular mechanism subserving associative learning.

Teaching design of innovation experiment for closed-loop control of optogenetics / 中华医学教育探索杂志

Combining with advances in optogenetics and feedback control of physiological function, we have utilized self-made PPDP (preview, presentation, demonstration, promotion) teaching method to clarify how various physiological functions are regulated by the nervous system and carried out physiological innovation experiment activities. The innovative experiments aim to cultivate students' self-study capability, broaden their vision, enhance their interest in physiology, and finally promote the effect of physiological theory teaching. We herein summarize our practice of closed-loop control of innovative experimental teaching in optogenetics from the following four facets: education concept, students and teacher resources, teaching design, and teaching experience. This summary is trying to explore new experiences of promoting students' participation in teaching activities and improving the teaching quality of physiology.

Design and validation of antibacterial and pH response of cationic guar gum film by combining hydroxyethyl cellulose and red cabbage pigment.

A simple and feasible method was adopted to construct the antibacterial and pH response of cationic guar gum (CGG) composite films (CGG-HEC, RC) through using hydroxyethyl cellulose (HEC) as an enhancer and red cabbage (RC) as a smart active substance. The effect of different HEC content on the binary composite films (CGG-HEC) performance shows that the highest tensile strength (51.59 MPa) can be obtained by adding 10% HEC due to the good compatibility between CGG and HEC. The ternary composite film (RC3) with 10% HEC and 3% RC addition has good performance in all aspects, such as high tensile strength (65.41 MPa), appropriate water vapor transmission coefficient (1.08), and good thermodynamic stability. In addition, RC3 has good antibacterial properties against E. coli and Staphylococcus aureus, taking advantage of the antibacterial properties of CGG and RC. RC3 can respond to changes in environmental pH and has a significant color change, and also has a significant color change when detecting the deterioration of pork and soy milk. Therefore, the ternary composite film (RC3) has good mechanical properties, antibacterial and intelligent response characteristics, and may be used in intelligent antibacterial packaging.

A brief introduction of Xiangya's anti-epidemic history in a century / 中南大学学报(医学版)

Based on archival materials, the Xiangya's anti-epidemic history in a century from its establishment to 2020 is divided into 4 stages. The first stage (1906-1926), Edward Hicks Hume and YAN Fuqing, the founders of Xiangya, prevented and controlled smallpox and plague. The second stage (1929-1953), during the resumption of Xiangya, students prevented and controlled cholera, plague, dysentery, typhus, and other infectious diseases. In the third stage (1953-1999), in a peacetime, Xiangya actively fought against schistosomiasis, hydatidosis, malaria, leprosy, tuberculosis and other epidemics. The fourth stage (2000-2020), the era of Central South University. Medical staff in Xiangya fight SARS, influenza A (HN) flu, Ebola hemorrhagic fever, coronavirus disease 2019, etc. Over the past hundred years, Xiangya people joined together to spread benevolence and love, apply medical knowledge and skills, combat the epidemic and rescue people in difficulties, which made a great contribution to the motherland and the people.

Advance in Language Development of Hearing-impaired Children / 中国康复理论与实践

The language of hearing-impaired children is poorly developed. There is a lagging development of spoken language, which is manifested in pronunciation, grammar and pragmatics. Written language has difficulties in understanding and expression. Sign language develops normally, but it affects the spoken and written language of hearing-impaired children. This paper summarized the interventions, such as medicine, speech and family, according to the law of language development of children, in order to provide reference for the study and intervention of language development for hearing-impaired children.

Progress in study on the role of metabolomics in toxic effects of environmental pollutants and the underlying mechanism / 中南大学学报(医学版)

Metabolomics methods were applied in the study of the toxicity of environmental pollutants. It has been shown that exposure to heavy metals such as mercury, arsenic, cadmium, chromium and lead could cause significant changes in energy, lipids, nucleic acids and amino acids in mammalian cells. After exposure to benzo(a)pyrene [B(a)P], the glands of Pinctada pumila could produce various changes, such as energy metabolic disorder, cell damage, signal transduction disorder, oxidative stress and osmotic disorder. Persistent organic compounds polychlorinated biphenyls (PCBs) could exert toxic effects on Zebrafish embryos through affecting amino acid metabolism, DNA and protein methylation and biosynthesis. After exposure to endocrine disruptors, such as nonylphenol, octylenediester phthalate and bisphenol propane, goldfish showed energy, lipid and nucleic acid metabolic disorders.

Detection and Analysis of Candida Albicans Enolase Antigen-Specific T Cells in Heathy Individuals by ELISPOT Assay / 现代检验医学杂志

Objective To observe the T cells immune response to Enolase (Eno),an immunodominant antigen of Candida albicans.Methods Determined the frequencies of positive spot-forming cells (SFCs) of Eno antigen-specific T cells secreting IFN-γ,IL-4 and IL-17A in the PBMCs of 25 healthy individuals by ELISPOT assay.Results After Eno stimulation,the SFCs of IFN-γ,IL-4 and IL 17A in 25 healthy persons were 14.00(8.50,39.00),0(0,0) and 2(1,4.50),respectively.Either the SFCs of IFN-γ or those of IL-17A were significantly higher than those of IL-4 (P＜0.05).The difference between SFCs of IFN-γ and those of IL-17A was also significant (P=0).The response rates of IFN-γ,IL-4 and IL-17A were 100％ (25/25),4.00％ (1/25) and 88.00％ (22/25),respectively.The difference between either IFN-γor IL 17A and IL-4 was significant (values all P＜0.05).Eno induced strong response (SCFs≥20) for IFN-γ in 10 healthy individuals (40.00％,10/25),but failed to induce strong response for IL-17A and IL-4 in all the volunteers.Major healthy individuals (84.00％,21/25)showed both Th1 and Th17 cells response against Eno,12.00％ (3/25) showing Th1 cells response in isolation,and none showed Th2 or Th17 cells response individually.Conclusion Eno of Candida albicans could induce immunodominant responses of Th1 and Th17 cells,which was considered to provide protection to IC.Eno might be a potential protective vaccine against IC.

Epigenetic changes in cytochrome P450 and indirect carcinogen carcinogenesis:a review / 中国药理学与毒理学杂志

Cytochrome P450(CYP450),one of the most important enzymes in the human body,medi?ates the activation and toxicity of indirect poisons as well as indirect carcinogens. CYP450 is a super?family mainly composed of CYP1A, CYP1B, CYP2A, CYP2B, CYP2C, CYP2E, CYP2W, CYP3A and their activities are widely modulated by epigenetic manners, such as DNA methylation, histone modifi?cation and microRNA interference.Indirect carcinogens including benzo(a)pyrene,2,3,7,8-tetrachlorod?ibenzo-p-dioxin,diethylstilbestrol,aflatoxin B1 and cyclophosphamide,can change epigenetic modifica?tions, such as specific changes in DNA methylation, histone acetylation, methylation or ubiquitination, and up-or down-regulation of microRNA expression,which affect the function of the major subtypes of CYP450 and their role in indirect carcinogen activation.

Analysis of mutations of 4 common genes among 216 patients with non-syndromic hearing impairment / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To explore the characteristics of mutations 4 common deafness-related genes among 216 patients from Shanghai area with non-syndromic hearing impairment (NSHI).</p><p><b>METHODS</b>Thirteen mutation sites in the four genes, namely GJB2 (c.35delG, c.176del16, c.235delC, c.299delAT, and c.155delTCTG), SLC26A4 (c.IVS7-2A>G, c.2168A>G, and c.1229C>T), mtDNA 12SrRNA (m.1494C>T, m.1555A>G, m.7445A>G, and m.12201T>C) and GJB3 (c.538C>T) were detected among the 216 patients and 41 individuals with normal hearing. The frequency and types of mutations were compared between the two groups.</p><p><b>RESULTS</b>Among the 216 NSHI patients, the total detection rate was 16.20% (35/216). GJB2 mutations were found in 17(7.87%) of the 216 patients, which included 5 cases with homozygous c.235delC mutation, 5 with homozygous c.235delC mutation, 1 with homozygous c.299delAT mutation, and 1 with homozygous c.299delAT mutation. c.235delC and 299delAT mutations were found in 5 cases. SLC26A4 mutation was found in 12(5.56%) of the 216 patients, which included 2 cases with homozygous c.IVS7-2A>G mutation, 9 with homozygous c.IVS7-2A>G mutation, and 1 with homozygous c.2168A>G mutation. Homogeneous mtDNA 12SrRNA m.1555A>G mutation was found in 6(2.78%) of the 216 patients. No GJB3 gene mutation was detected. No mutation of the 4 genes were detected in the 41 individuals with normal hearing. In 2 cases of the 12 patients with SLC26A4 gene mutation, CT scan of the temporal bone has confirmed expansion of vestibular aqueduct.</p><p><b>CONCLUSION</b>Above results indicated that GJB2 and SLC26A4 were the major genes involved with hearing loss in Shanghai area.</p>

Relationship between the gene polymorphisms of oxidative metabolism enzyme of exogenous chemicals and the susceptibility to neoplasms / 中南大学学报(医学版)

The gene polymorphisms of human being will cause abnormality in the expression of corresponding gene,which is closely related to the physiological function and disease.Cytochrome P450,cyclooxygenase and lipoxygenase are vital enzymes that mediated the oxidative metabolism process for exogenous chemicals,and play important roles in activating the indirect carcinogens and metabolizing clinical drug;the gene polymorphisms of these enzymes can change the expression and activity of enzymes,affect the metabolic transformation of carcinogens,and then give rise to difference in the susceptibility to neoplasms.Studying the relationship between the gene polymorphisms of oxidative metabolism enzyme for endogenous and exogenous chemicals and the susceptibility to neoplasms can provide scientific basis for probing into the genetic markers and the pathogenesis of neoplasms.