Discovery of cinnamamide/ester triazole hybrids as potential treatment for Alzheimer's disease.

Developing multitargeted ligands as promising therapeutics for Alzheimer's disease (AD) has been considered important. Herein, a novel class of cinnamamide/ester-triazole hybrids with multifaceted effects on AD was developed based on the multitarget-directed ligands strategy. Thirty-seven cinnamamide/ester-triazole hybrids were synthesized, with most exhibiting significant inhibitory activity against Aß-induced toxicity at a single concentration in vitro. The most optimal hybrid compound 4j inhibited copper-induced Aß toxicity in AD cells. its action was superior to that of donepezil and memantine. It also moderately inhibited intracellular AChE activity and presented favorable bioavailability and blood-brain barrier penetration with low toxicity in vivo. Of note, it ameliorated cognitive impairment, neuronal degeneration, and Aß deposition in Aß1-42-injured mice. Mechanistically, the compound regulated APP processing by promoting the ADAM10-associated nonamyloidogenic signaling and inhibiting the BACE1-mediated amyloidogenic pathway. Moreover, it suppressed intracellular AChE activity and tau phosphorylation. Therefore, compound 4j may be a promising multitargeted active molecule against AD.

Variation in the Distribution of Large-scale Spatiotemporal Patterns of Activity Across Brain States.

A few large-scale spatiotemporal patterns of brain activity (quasiperiodic patterns or QPPs) account for most of the spatial structure observed in resting state functional magnetic resonance imaging (rs-fMRI). The QPPs capture well-known features such as the evolution of the global signal and the alternating dominance of the default mode and task positive networks. These widespread patterns of activity have plausible ties to neuromodulatory input that mediates changes in nonlocalized processes, including arousal and attention. To determine whether QPPs exhibit variations across brain conditions, the relative magnitude and distribution of the three strongest QPPs were examined in two scenarios. First, in data from the Human Connectome Project, the relative incidence and magnitude of the QPPs was examined over the course of the scan, under the hypothesis that increasing drowsiness would shift the expression of the QPPs over time. Second, using rs-fMRI in rats obtained with a novel approach that minimizes noise, the relative incidence and magnitude of the QPPs was examined under three different anesthetic conditions expected to create distinct types of brain activity. The results indicate that both the distribution of QPPs and their magnitude changes with brain state, evidence of the sensitivity of these large-scale patterns to widespread changes linked to alterations in brain conditions.

Development of a thermotaxis and rheotaxis microfluidic device for motile spermatozoa sorting.

Male infertility is a pervasive global reproductive challenge, primarily attributed to a decline in semen quality. Addressing this concern, there has been a growing focus on spermatozoa sorting in assisted reproductive technology. This study introduces a groundbreaking development in the form of a thermotaxis and rheotaxis microfluidic (TRMC) device designed for efficient motile spermatozoa sorting within a short 15-min timeframe. The TRMC device mimics the natural sperm sorting mechanism of the oviduct, selecting spermatozoa with superior motility and DNA integrity. The experimental outcomes demonstrate a remarkable enhancement in the percentage of progressive spermatozoa following sorting, soaring from 3.90% to an impressive 96.11% when subjected to a temperature decrease from 38 °C to 35 °C. Notably, sperm motility exhibited a substantial 69% improvement. The TRMC device exhibited a commendable recovery rate of 60.93%, surpassing current clinical requirements. Furthermore, the sorted spermatozoa displayed a notable reduction in the DNA fragmentation index to 6.94%, signifying a substantial 90% enhancement in DNA integrity. This remarkable advancement positions the TRMC device as highly suitable for applications in in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI), offering a promising solution to male infertility challenges.

Foliar uptake screening: A promising strategy for identifying wheat varieties with low lead accumulation.

Lead (Pb) contamination in wheat grain is of great concern, especially in North China. Atmospheric deposition is a major contributor to Pb accumulation in wheat grain. Screening low Pb accumulating wheat varieties has been an effective method for addressing Pb contamination in wheat grain. However, identifying wheat varieties with low Pb accumulation based on foliar uptake of atmospheric Pb has been neglected. Therefore, two field trials with distinct atmospheric Pb deposition were conducted to screen for stable varieties with low Pb accumulation. It was verified that YB700 and CH58, which have high thousand-grain weights and stable low Pb accumulation in field 1 (0.19 and 0.13 mg kg-1) and field 2 (0.17 and 0.20 mg kg-1), respectively, were recommended for cultivation in atmospheric Pb contaminated farmlands in North China. Furthermore, indoor experiments were conducted to investigate Pb uptake by the roots and leaves of different wheat varieties. Our findings indicate that Pb accumulation in different wheat varieties is primarily influenced by foliar Pb uptake rather than root Pb uptake. Interestingly, there was a positive correlation (p < 0.05) between the Pb concentrations in leaves and the stomatal width and trichome length of the adaxial epidermal surface. Additionally, there is a positive correlation (p < 0.01) between the Pb concentration in the wheat grain and trichome length. In conclusion, the screening of wheat varieties with narrower stomatal widths or shorter trichomes based on foliar uptake pathways is an effective strategy for ensuring food safety in areas contaminated by atmospheric Pb.

Are plain language summaries more readable than scientific abstracts? Evidence from six biomedical and life sciences journals.

In recent decades, members of the general public have become increasingly reliant on findings of scientific studies for decision-making. However, scientific writing usually features a heavy use of technical language, which may pose challenges for people outside of the scientific community. To alleviate this issue, plain language summaries were introduced to provide a brief summary of scientific papers in clear and accessible language. Despite increasing attention paid to the research of plain language summaries, little is known about whether these summaries are readable for the intended audiences. Based on a large corpus sampled from six biomedical and life sciences journals, the present study examined the readability and jargon use of plain language summaries and scientific abstracts on a technical level. It was found that (1) plain language summaries were more readable than scientific abstracts, (2) the reading grade levels of plain language summaries were moderately correlated with that of scientific abstracts, (3) researchers used less jargon in plain language summaries than in scientific abstracts, and (4) the readability of and the jargon use in both plain language summaries and scientific abstracts exceeded the recommended threshold for the general public. The findings were discussed with possible explanations. Implications for academic writing and scientific communication were offered.

The biocontrol potentials of rhizospheric bacterium Bacillus velezensis K0T24 against mulberry bacterial wilt disease.

Mulberry bacterial wilt disease, caused by Ralstonia pseudosolanacearum, is a devastating soil-borne disease in the silk-mulberry-related industry. In this study, through high-throughput sequencing, we compared the rhizosphere bacterial composition of the mulberry-resistant cultivar (K10) and susceptible cultivar (G12), confirming Bacillus as a genus-level biomarker for K10. Next, twelve Bacillus spp. isolates, derived from the rhizosphere of K10, were screened for their antagonistic activity against R. pseudosolanacearum. The isolate showing strong antagonism was identified as B. velezensis K0T24 and selected for further analysis. The fermentation supernatant of B. velezensis K0T24 significantly inhibited the growth of R. pseudosolanacearum (82.47%) and the expression of its pathogenic genes. Using B. velezensis K0T24 in mulberry seedlings also increased defense enzyme activities and achieved a control efficacy of up to 55.17% against mulberry bacterial wilt disease. Collectively, our findings demonstrate the potential of B. velezensis K0T24 in suppressing mulberry bacterial wilt disease.

MDKLoss: Medicine domain knowledge loss for skin lesion recognition.

Methods based on deep learning have shown good advantages in skin lesion recognition. However, the diversity of lesion shapes and the influence of noise disturbances such as hair, bubbles, and markers leads to large intra-class differences and small inter-class similarities, which existing methods have not yet effectively resolved. In addition, most existing methods enhance the performance of skin lesion recognition by improving deep learning models without considering the guidance of medical knowledge of skin lesions. In this paper, we innovatively construct feature associations between different lesions using medical knowledge, and design a medical domain knowledge loss function (MDKLoss) based on these associations. By expanding the gap between samples of various lesion categories, MDKLoss enhances the capacity of deep learning models to differentiate between different lesions and consequently boosts classification performance. Extensive experiments on ISIC2018 and ISIC2019 datasets show that the proposed method achieves a maximum of 91.6% and 87.6% accuracy. Furthermore, compared with existing state-of-the-art loss functions, the proposed method demonstrates its effectiveness, universality, and superiority.

[Blocking Effects of Foliar Conditioners on Cadmium, Arsenic, and Lead Accumulation in Wheat Grain in Compound-contaminated Farmland].

Heavy metal contamination of soil has become a hot issue of social concern due to its impact on the safety of agricultural products in recent years. Wheat is one of the most dominant staple food crops worldwide and has become a major source of toxic metals in human diets. Foliar application was considered to be a more efficient and economical method of heavy metal remediation. Field experiments were carried out in Cd-, As-, and Pb-contaminated farmland soils. The effects of foliar conditioners on the accumulation of Cd, As, and Pb in wheat grains were investigated after being sprayed with Zn (0.2% ZnSO4), Mg (0.4% MgSO4), and Mn (0.2% MnSO4) separately and in combination. Thus, the effective foliar conditioners were selected to block the accumulation of Cd, As, and Pb in wheat grains grown in combined heavy metal-contaminated farmland in north China. The results showed that, compared with that in the control, the Cd, As, and Pb contents in wheat grains of the Zn+Mg+Mn foliar treatment were significantly decreased by 18.96%, 23.87%, and 51.31%, respectively, and TFgrain/straw decreased by 14.62%, 27.73%, and 47.70%, respectively. Thus, spraying the compound foliar conditioner of Zn+Mg+Mn could effectively reduce heavy metal accumulation in wheat grains through inhibition translocation of those metals from stem leaves to grain. In addition, the results indicated that Cd and As were mainly distributed at the central endosperm (34.08%-37.08%), whereas Pb was primarily distributed at the pericarp and seed coat (27.78%) of the wheat grain. Compared with that in the control, spraying the compound foliar conditioner of Zn+Mg+Mn extremely decreased Cd and As accumulation in the aleurone layer of the wheat grain by 81.10% and 82.24%, respectively. Except for the pericarp, seed coat, and central endosperm layers, the Pb content in each grain layer was dramatically decreased by 42.85% to 91.15%. There was only a significant negative correlation between heavy metal content and Zn content in the aleurone layer (P2) of wheat flour. In summary, the accumulation of Cd, As, and Pb in wheat grains, especially in the aleurone layer, could be effectively reduced by foliar conditioner application at the jointing, booting, and early filling stages of wheat, separately. Furthermore, besides the foliar treatment, removing wheat bran to reduce Cd contamination in wheat grains is highly recommended to ensure the safe production of wheat.

Changes in macrophage infiltration and podocyte injury in lupus nephritis patients with repeated renal biopsy: Report of three cases.

BACKGROUND: In this study, we retrospectively analysed macrophage infiltration and podocyte injury in three patients with diffuse proliferative lupus nephritis (LN) who underwent repeated renal biopsy. CASE SUMMARY: Clinical data of three diffuse proliferative LN patients with different pathological characteristics (case 1 was LN IV-G (A), case 2 was LN IV-G (A) + V, and case 3 was LN IV-G (A) + thrombotic microangiopathy) were reviewed. All patients underwent repeated renal biopsies 6 mo later, and renal biopsy specimens were studied. Macrophage infiltration was assessed by CD68 expression detected by immunohistochemical staining, and an immunofluorescence assay was used to detect podocin expression to assess podocyte damage. After treatment, Case 1 changed to LN III-(A), Case 2 remained as type V LN lesions, and Case 3, which changed to LN IV-S (A), had the worst prognosis. We observed reduced macrophage infiltration after therapy. However, two of the patients with active lesions after treatment still showed macrophage infiltration in the renal interstitium. Before treatment, the three patients showed discontinuous expression of podocin. Notably, the integrity of podocin was restored after treatment in Case 1. CONCLUSION: It may be possible to reverse podocyte damage and decrease the infiltrating macrophages in LN patients through effective treatment.

Ectopic expression of a bacterial thiamin monophosphate kinase enhances vitamin B1 biosynthesis in plants.

Plants and bacteria have distinct pathways to synthesize the bioactive vitamin B1 thiamin diphosphate (TDP). In plants, thiamin monophosphate (TMP) synthesized in the TDP biosynthetic pathway is first converted to thiamin by a phosphatase, which is then pyrophosphorylated to TDP. In contrast, bacteria use a TMP kinase encoded by ThiL to phosphorylate TMP to TDP directly. The Arabidopsis THIAMIN REQUIRING2 (TH2)-encoded phosphatase is involved in TDP biosynthesis. The chlorotic th2 mutants have high TMP and low thiamin and TDP. Ectopic expression of Escherichia coli ThiL and ThiL-GFP rescued the th2-3 mutant, suggesting that the bacterial TMP kinase could directly convert TMP into TDP in Arabidopsis. These results provide direct evidence that the chlorotic phenotype of th2-3 is caused by TDP rather than thiamin deficiency. Transgenic Arabidopsis harboring engineered ThiL-GFP targeting to the cytosol, chloroplast, mitochondrion, or nucleus accumulated higher TDP than the wild type (WT). Ectopic expression of E. coli ThiL driven by the UBIQUITIN (UBI) promoter or an endosperm-specific GLUTELIN1 (GT1) promoter also enhanced TDP biosynthesis in rice. The pUBI:ThiL transgenic rice accumulated more TDP and total vitamin B1 in the leaves, and the pGT1:ThiL transgenic lines had higher TDP and total vitamin B1 in the seeds than the WT. Total vitamin B1 only increased by approximately 25-30% in the polished and unpolished seeds of the pGT1:ThiL transgenic rice compared to the WT. Nevertheless, these results suggest that genetic engineering of a bacterial vitamin B1 biosynthetic gene downstream of TMP can enhance vitamin B1 production in rice.

Knockdown of FOXRED2 restrains proliferation, invasion and migration of human melanoma cells.

Objectives: This experiment investigated the role of the FAD-dependent oxidoreductase domain-containing 2 (FOXRED2) in the development of cutaneous malignant melanoma. Methods: We explored the expression and prognostic effects of FOXRED2 in cutaneous malignant melanoma by performing bioinformatics analyses and immunohistochemical staining experiments and verified the biological influence of FOXRED2 on human melanoma cells using in vitro experiments. Results: FOXRED2 expression was significantly higher in cutaneous malignant melanoma compared to normal skin and nevus tissues and closely associated with prognosis. The expression levels of FOXRED2 mRNA and protein were significantly upregulated in human melanoma cell lines, and knocking down FOXRED2 expression inhibits proliferation, invasion, and migration, promotes apoptosis, and alters tumor cell biology in A2058 and A375 cells. Conclusion: FOXRED2 may play a crucial role in the development and progression of cutaneous malignant melanoma.

Imidazolone as an Amide Bioisostere in the Development of ß-1,3-N-Acetylglucosaminyltransferase 2 (B3GNT2) Inhibitors.

B3GNT2 is responsible for elongation of cell surface long-chain polylactosamine, which influences the regulation of the immune response, making it an attractive target for immunomodulation. In the development of amide containing B3GNT2 inhibitors guided by structure-based drug design, imidazolones were found to successfully serve as amide bioisosteres. This novel imidazolone isosteric strategy alleviated torsional strain of the amide bond on binding to B3GNT2 and improved potency, isoform selectivity, as well as certain physicochemical and pharmacokinetic properties. Herein, we present the synthesis, SAR, X-ray cocrystal structures, and in vivo PK properties of imidazol-4-ones in the context of B3GNT2 inhibition.

[Distribution and Transport of Cadmium and Arsenic in Different Aboveground Parts of Wheat After Flowering].

To investigate the effects of leaves and stems on the accumulation and transport of cadmium(Cd) and arsenic(As) in wheat shoots after flowering, a field experiment was conducted in a typical Cd and As co-contaminated agricultural land to explore the distribution and translocation of Cd and As in the different parts of two wheat cultivars after flowering. The results showed that Cd was mainly distributed in the nodes of two varieties, and the translocation factors of Cd from internode 3 to node 2, from internode 2 to node 1, and from sheath 1 to node 1 were markedly higher than those of other aboveground parts during the grain-filling stage. However, Cd was mainly distributed in the leaves, and the translocation factors of Cd from sheath to leaf and from node 1 to rachis was significantly higher than those of other parts at the mature stage. In addition, the transport capacity of Cd from glume to rachis and from rachis to grain in JM22 was significantly lower than that in SN28, which significantly reduced Cd concentrations in the rachis, glume, and grain of JM22 by 22.3%, 40.8%, and 44.4%, respectively. Meanwhile, As was mainly distributed in the wheat leaves from the grain-filling stage to the mature stage, and As concentrations in the glume and grain of JM22 were 25.8% and 33.3% lower than those of SN28, respectively. Additionally, the translocation factors of As from the sheath to the node were significantly 438% and 190% higher than that from leaf to sheath and from node to internode during the whole grain filling stage and mature stage. Moreover, the translocation factors of As from glumes to grains and from rachis to grains in JM22 were 40.6% and 44.4% lower than that in SN28, respectively. In summary, flag leaf, node 1, and the rachis had regulated Cd transport and accumulation in wheat grains, whereas leaf 3, flag leaf, node 1, the glumes, and the rachis were mainly responsible for As transport and accumulation in wheat grains.

[Comparison of early clinical outcomes between SuperCap and direct anterior approaches for total hip arthroplasty].

OBJECTIVE: To compare the short-term clinical efficacy of SuperCap approach and direct anterior approach in total hip arthroplasty. METHODS: Clinical data of 70 patients who underwent minimally invasive SuperCap approach and DAA THA in January 2016 to June 2017 were retrospective analyzed. These patients were divided into two groups:SuperCap approach group(SuperCap group) and direct anterior approach group(DAA group). There were 15 males and 15 females in SuperCap group, aged from 45 to 71 years old, and the follow-up time ranged from 24 to 30 months. There were 24 males and 16 females in Group B, aged from 51 to 76 years and the follow-up time ranged from 24 to 36 months. Hemoglobin level of the 3rd day after operation, transfusion rate, acetabular abduction angle, anteversion angle and creatine kinase level of the 3rd day after operation, Harris score of 3 months and the last time, VAS score of 1 week and the last time were recorded and compared. Complications were recorded at the final follow-up. RESULTS: All patients were followed up, the follow-up time of SuperCap group ranged from 24 to 30 months, that of DAA group ranged from 24 to 36 months. No significant differences were found in hemoglobin level on the 3rd day after operation, transfusion rate, Harris score or VAS score between two group (P>0.05). There was no significant difference in Harris score between 3 months after operation and the final follow-up in both groups (P>0.05). There were no significant difference in VAS scores of 6 weeks after operation and on the final follow-up neither(P>0.05). The level of creatine kinase in SuperCap group was significant lower than that in DAA group(P<0.05). Until the final follow-up, there was no significant difference in the incidence of complications between the two groups(P>0.05). CONCLUSION: The clinical effect of minimally invasive SuperCap approach after total hip arthroplasty is comparable to that of DAA approach with less soft tissue injury. Patients can recover rapidly after operation and it is a safe and effective surgical approach for surgeons with short learning curve.

Comparison of five retinoids for anti-photoaging therapy: Evaluation of anti-inflammatory and anti-oxidative activities in vitro and therapeutic efficacy in vivo.

Over the past decades, increasing evidences have demonstrated that five retinoids, including retinol (ROL), retinol acetate (RAc), retinol propionate (RP), retinol palmitate (RPalm), and hydroxypinacolone retinoate (HPR), can be potential therapeutic agents for skin photoaging. However, therapeutic efficacies and biosafety have never been compared to these compounds. This study aimed to determine the optimal retinoid type(s) for anti-photoaging therapy both in vitro and in vivo. Our data demonstrated that four retinoids (RPalm, RP, HPR and ROL) but not RAc were effective for anti-photoaging treatment at 5 µg/mL in vitro, with action mechanisms associated with antioxidative, anti-inflammatory and anti-skin ECM degradation activities. Notably, both RPalm and RP appeared superior to HPR and ROL for those activities. Importantly, both RPalm and RP were shown to be optimal for anti-photoaging therapy when topically applied at 5 mg/kg in a UVB-induced mice model of photoaging, which is consistent with their high anti-photoaging activities in vitro. Additionally, topical application of these five retinoids showed satisfactory biosafety without causing significant apoptosis in animal organs, although RP application led to a slight decline in animal body weights. Collectively, these data have laid a good foundation for the next development of the clinical application of these retinoids for skin healthcare.

[Application of stable isotope techniques in soil food web research]. / ç¨³å®šåŒä½ç´ æŠ€æœ¯åœ¨åœŸå£¤é£Ÿç‰©ç½‘ç ”ç©¶ä¸­çš„åº”ç”¨.

Stable isotope technique is important for understanding the structure and function of soil food web, which is considered as a belowground black box. We reviewed typical application cases of stable isotope techniques in the research of soil food webs, including to determine food sources and feeding preferences of soil fauna by using isotopes, and to analyze the trophic structure of soil food webs through isotope fractionation effects during the process of feeding and nutrient sequestration by soil fauna. Additionally, stable isotope techniques could reveal the role of soil biota at different trophic levels within soil food web in ecosystem matter and energy flow, which favored to carry out accurate and efficient research on the contribution of soil food webs to soil carbon and nitrogen cycling process and the corresponding influence mechanism. We further put forward the limitations of current stable isotope techniques and the future development directions.

[Effects of Straw Returning with Lime on SOC and Carbon Pool Management in Acidic Paddy Soil].

Soil acidification and low SOC are the main limiting factors in acidic paddy soils. Straw returning with lime is an effective measure to alleviate soil acidification and improve soil fertility; however, its interaction effects on SOC and carbon pool management are still unclear. To investigate the impact of straw returning with lime on the organic carbon pool of acidic paddy soil, field experiments were conducted on acidic paddy soil in Baiyun District and Huiyang District of Guangdong Province. The changes in soil total organic carbon (TOC), water-soluble organic carbon (DOC), active organic carbon (LOC), particulate organic carbon (POC), microbial biomass carbon (MBC), carbon pool index (CPI), stable organic carbon (IOC), carbon pool activity (L), carbon pool activity index (CPAI), and carbon pool management index (CPMI) were analyzed under three treatments (CK, conventional fertilization; RS, straw returning+conventional fertilization; RS+L straw returning with lime+conventional fertilization). The results demonstrated that compared with that in CK, the TOC, LOC, POC, and MBC in the RS+L treatment were significantly increased by 10.24%-17.79%, 34.49%-44.37%, 19.27%-23.59%, and 33.36%-43.26%, respectively (P<0.05). Compared with that in CK, the RS+L treatment significantly increased the DOC content during the early growth stage (15-45 days after transplanting) of rice (P<0.05) but had no significant influence on the DOC content during the late growth stage of rice. Compared with that in RS, the TOC, LOC, POC, and MBC in the RS+L treatment were increased by 2.15%-6.95%, 1.17%-17.90%, 4.27%-8.65%, and 12.99%-14.53%, respectively. Compared with that in CK, the RS+L treatment significantly increased IOC and CPI by 8.32%-15.57% and 14.00%-20.00%, respectively (P<0.05). Compared with that in the CK treatment, the RS treatment significantly increased CPI by 14.00%-18.00% (P<0.05). No significant differences in L, CPAI, or CPMI were detected among the different treatments. The soil pH in the RS+L treatment was significantly higher than that in the CK treatment (P<0.05). No significant differences in rice yield were detected among the different treatments. Principal component analysis demonstrated that rice yield was primarily correlated with DOC, LOC, CPAI, and CPMI but its contribution to SOC and carbon pool management index was low. Principal component analysis also indicated that straw returning with lime could improve soil pH and nutrient contents of acidic paddy soil, driving the formation and accumulation of organic carbon fraction such as MBC and POC, thus boosting the increase in SOC. In conclusion, straw returning with lime is beneficial to the accumulation of MBC, POC, LOC, and IOC in acidic paddy soil to improve the content and stability of soil total organic carbon, which is an effective way to improve the carbon sequestration of acidic paddy soil.