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Identified as the pathogenic genes of Alzheimer's disease (AD), APP, PSEN1, and PSEN2 mainly lead to early-onset AD, whose course is more aggressive, and atypical symptoms are more common than sporadic AD. Here, a novel missense mutation, APP E674Q (also named “Shanghai APP”), was detected in a Chinese index patient with typical late-onset AD (LOAD) who developed memory decline in his mid-70s. The results from neuroimaging were consistent with AD, where widespread amyloid β deposition was demonstrated in 18F-florbetapir Positron Emission Tomography (PET). APP E674Q is close to the β-secretase cleavage site and the well-studied Swedish APP mutation (KM670/671NL), which was predicted to be pathogenic in silico. Molecular dynamics simulation indicated that the E674Q mutation resulted in a rearrangement of the interaction mode between APP and BACE1 and that the E674Q mutation was more prone to cleavage by BACE1. The in vitro results suggested that the E674Q mutation was pathogenic by facilitating the BACE1-mediated processing of APP and the production of Aβ. Furthermore, we applied an adeno-associated virus (AAV)-mediated transfer of the human E674Q mutant APP gene to the hippocampi of two-month-old C57Bl/6 J mice. AAV-E674Q-injected mice exhibited impaired learning behavior and increased pathological burden in the brain, implying that the E674Q mutation had a pathogenicity that bore a comparison with the classical Swedish mutation. Collectively, we report a strong amyloidogenic effect of the E674Q substitution in AD. To our knowledge, E674Q is the only pathogenic mutation within the amyloid processing sequence causing LOAD.

Chouioia cunea are known to exploit in varying degrees a wide range of lepidopteran species and its offspring development may vary with host species. This study examined its preimaginal development and larval gut microbiota in parasitizing five folivorous lepidopteran hosts including Hyphantria cunea (referred to thereafter as CcHc), Antherea pernyi (CcAp), Helicoverpa armigera (CcHa), Spodoptera exigua (CcSe), and Spodoptera frugiperda (CcSf). Though rates of parasitism and offspring eclosion did not change with host species, the development period and number of offspring eclosed varied with hosts, with the shortest period in CcSf and the highest number from CcAp. For offspring larval gut microbiota, though phylum Proteobacteria was dominant for attacking CcAp, Firmicutes was so for the other hosts. All microbial genera except Enterococcus were less abundant for CcSf than the other hosts. The database-based predictions indicate a significant positive correlation between Cutibacterium and Aureimonas with the relative number of wasp emergence, while Blastomonas exhibits a strong positive association with the developmental period. Our results imply the potential relevance of the gut microbial community in offspring larvae to host species attacked by C. cunea.

Insufficient milk supply is a widespread issue faced by women globally and associated with a higher risk of health problems in infants and mothers. Hemerocallis citrina Baron, commonly known as daylily, is a perennial edible plant often used in traditional Asian cuisine to promote lactation. However, the active compound(s) and mechanism of its lactation-promoting effect remain unclear. This study aimed to confirm the traditional use of daylily in promoting lactation and investigate its potential active components and underlying molecular mechanisms. Our results showed that the aqueous extracts of H. citrina Baroni (HAE) significantly enhanced milk production, and the serum levels of lactation-related hormones, and promoted mammary gland development in lactating rats, as well as increased the levels of milk components in bovine mammary epithelial cells (BMECs) (p < 0.05). UHPLC-Q-Exactive Orbitrap-MS analysis revealed that hexamethylquercetin (HQ) is the representative flavonoid component in HAE, accounting for 42.66% of the total flavonoids. An integrated network pharmacology and molecular docking analysis suggested that HQ may be the potential active flavonoid in HAE that promotes lactation, possibly supporting lactation by binding to key target proteins such as STAT5A, PIK3CA, IGF1R, TP53, CCND1, BCL2, INS, AR, and DLD. Cell experiments further demonstrated that HQ could promote cell proliferation and the synthesis of milk proteins, lactose, and milk fat in BMECs. Transcriptomic analysis combined with a quantitative reverse transcription polymerase chain reaction (RT-qPCR) revealed that both HAE and HQ exert a lactation-promoting function mainly through regulating the expression of key genes in the PI3K-Akt signaling pathway.

Wild-type strains hardly meet the current industrial demands due to low stability. The performance of microbial strains (high-yielding, high-quality strains) can be improved by using physical mutagenesis techniques. At the same time，high throughput screening methods and techniques can be used to quickly obtain ideal strains from the mutation library. However, traditional manual screening and shaker culture are high-cost, time-consuming, and laborious, and high-throughput screening technology can solve this problem. In this review, the applications of traditional and novel mutagenesis used for the improvement of probiotics are summarized, the principles of traditional and novel physical mutagenesis techniques are discussed, the differences between the two kinds of mutagenesis techniques are compared and their applications in the improvement of probiotics are described. At the same time, the characteristics and relevant applications of various high-throughput screening technologies (microtitration plate screening, fluorescence activated cell sorting, biosensors screening, droplet microfluidic platform screening and model animal platform screening) are summarized. This review provides important reference for reducing screening cost, improving screening efficiency and obtaining high yield ideal target strains.

ABSTRACT: Yak milk is rich in essential milk proteins of nutritional and therapeutic value. In this study, whey proteins of milk from 3 yak breeds (Gannan, GN; Huanhu, HH; Maiwa, MW) in China were comprehensively identified and compared using a data-independent acquisition quantitative proteomics approach. A total of 632 proteins were identified in yak milk whey samples, in which immune-related proteins were abundant. Compared with other milks, more proteins were involved in oxidation-reduction process and with ATP binding. In addition, we identified 96, 155, and 164 differentially expressed proteins (DEP) for GN versus HH, GN versus MW, and HH versus MW, respectively. “Phagosome” and “complement and coagulation cascades” were the most significant pathways for DEP of GN versus HH and GN or HH versus MW yak milk based on the Kyoto Encyclopedia of Genes and Genomes pathway analysis. Protein-protein interaction network analysis showed that DEP for the 3 comparisons had significant biological interactions but were associated with different functions. The results provide useful information on yak milk from different breeds in China, and elucidate the biological functions of yak milk proteins.

ObjectivesOne-carbon metabolism (OCM) significantly influences fetal growth and neurodevelopment through transferring methyl group to biomolecules, during which folate, methionine, choline and betaine function as methyl donor nutrients, while vitamin B2, B6, B12 function as enzyme cofactors, and homocysteine (Hcy) and S-adenosyl methionine (SAM) are functional metabolites. This study aimed to assess blood OCM index levels and explore their relationships among Chinese pregnant women.MethodsData were obtained from the baseline of the Mother–Child Nutrition and Health Cohort Study. Pregnant women, voluntarily recruited from September 2020 to June 2022 during antenatal examinations in five Chinese cities at 24–32 gestational weeks, provided fasting venous blood samples. Measurements included RBC and serum folate, serum vitamin B2, B6, B12, choline, betaine, methionine, total Hcy (tHcy), and plasma SAM. Sociodemographic characteristics and pregnancy-related conditions were collected via a self-designed questionnaire.ResultsOf 397 participants, 82.6% were in mid-pregnancy (24–27 gestational weeks) and 17.4% were in late-pregnancy (28–32 gestational weeks). Serum folate, vitamin B6, and B12 deficiencies were 2.5, 1.3, and 8.3%, respectively. Elevated tHcy (≥10 μmol/L) was observed in 1.8% of pregnant women. Elderly pregnant women (aged 35 and above) exhibited significantly lower serum methionine levels (p

With the continuous improvement of people's living standards and health awareness, more and more attention has been paid to food safety. It follows that the research and management of the types and labels of food allergens also need to be more and more strict. Therefore, the regulation of food allergens needs to be more and more stringent. This summary reviews the current status of food allergen testing methods and standards in China. Also, the labelling of food allergen types in China, the Codex Alimentarius Commission, the United States, the European Union, Canada and Japan is systematically summarized. By systematically reviewing the labeling management of food allergens in various countries and regions, it is hoped to provide reference for Chinese food allergen labeling management, and to continuously improve our country's food allergen detection methods and labeling standards.

IntroductionIn this paper, microbiota analysis was determined to analyze the structure and difference of intestinal microbiota between LBMJ (late-onset breast milk jaundice) infants and healthy individuals.MethodsWe collected fresh fecal samples from 13 infants with LBMJ and 13 healthy individuals, then determined the intestinal microbiota by 16 s rRNA sequencing. The differences of microbiota structure, diversity and functional characteristics between the two groups were analyzed, and the correlation between dominant genus and TcB (transcutaneous bilirubin) value was calculated.ResultsIn this study, there were no significant differences in maternal demographic characteristics, neonatal status and macronutrients in breast milk between the two groups (p > 0.05). There are differences in the structure of intestinal microbiota between LBMJ and the control group. At the genus level, the relative abundance of Klebsiella in the case group is high (p

In recent years, oncolytic viruses (OVs) have emerged as an effective means of treating cancer. OVs have multiple oncotherapeutic functions including specifically infecting and lysing tumor cells, initiating immune cell death, attacking and destroying tumor angiogenesis and triggering a broad bystander effect. Oncolytic viruses have been used in clinical trials and clinical treatment as drugs for cancer therapy, and as a result, oncolytic viruses are required to have long-term storage stability for clinical use. In the clinical application of oncolytic viruses, formulation design plays a decisive role in the stability of the virus. Therefore, this paper reviews the degradation factors and their degradation mechanisms (pH, thermal stress, freeze–thaw damage, surface adsorption, oxidation, etc.) faced by oncolytic viruses during storage, and it discusses how to rationally add excipients for the degradation mechanisms to achieve the purpose of maintaining the long-term stability of oncolytic viral activity. Finally, the formulation strategies for the long-term formulation stability of oncolytic viruses are discussed in terms of buffers, permeation agents, cryoprotectants, surfactants, free radical scavengers, and bulking agent based on virus degradation mechanisms.

Parkinson's disease (PD) is the most common motor-associated neurodegenerative disease. Although the pathogenesis of PD is still wrapped in the mist, accumulating evidence indicates that mitochondrial dysfunction contributes to the onset and progression of PD. We previously reported that the lysosomal protease asparagine endopeptidase (AEP) cleaves α-synuclein in the brains of PD patients. The major product, α-synuclein 1–103, significantly promotes PD-like histological changes and motor dysfunction. However, the underlying molecular mechanisms remain unknown. Here we show that α-synuclein 1–103 fragment interacts with mitochondria and induces morphological and functional abnormalities of mitochondria. Furthermore, we investigated the protective effects of 7,8-dihydroxyflavone (7,8-DHF) on mitochondrial dysfunction induced by α-synuclein 1–103 fragment. We found that 7,8-DHF ameliorated α-synuclein 1–103-induced mitochondrial impairment and motor dysfunction. These results indicate that 7,8-DHF represents a novel oral bioactive therapeutic agent for treating PD.

Abstract Background Maternal feeding anxiety (FA) was prevalent during puerperium and might affect infant feeding practices. This study was aimed to investigate the FA status in Chinese postpartum women and its relationship with infant feeding practices (FPs). Methods Participants were from the Mother-Infant Cohort Study of China, in which the dietary and feeding practices, physical and psychiatric health for both mothers and infants were followed up from childbirth to next 2 years. In this study the maternal feeding anxiety (FA) status at 0–3 months postpartum was assessed by Li’s Self-rating Feeding Anxiety Scale (SFAS). Infant feeding practices (FPs) at 0–3 months, including breastfeeding-related behaviors, responsive feeding and infant food refusal were investigated by self-designed questionnaire. Results In total 456 mothers the average feeding anxiety scores (FAS) was 41.02 ± 8.02 (mean ± SD), and maternal FA prevalence were 61.4% (FAS>38) with severe FA being 8.6% (FAS>52) at 0–3 months postpartum. The FAS was related with infant FPs, and lower maternal FAS was significantly related with infant colostrum feeding (40.86 ± 8.02 vs 44.74 ± 11.33, P 53) were more likely to feed infants with bottle (ORs, 95%CI: 2.41, 1.11 ~ 5.19). There were not significant association between FAS and exclusive breastfeeding and responsive feeding practices (P > 0.05). The higher FAS was associated with infant food refusal behaviors, the maternal scores whose infant “never”, “rarely”, “sometimes” and “often” spat out food when feeding were 39.86 ± 8.02, 41.47 ± 8.18, 41.36 ± 7.44 and 42.14 ± 12.03 increasingly (P > 0.05), and the FA prevalence was significantly different among groups (P

The FLT3-ITD mutation occurs in about 30% of acute myeloid leukemia (AML) and is associated with poor prognosis. However, FLT3 inhibitors are only partially effective and prone to acquired resistance. Here, we identified Yes-associated protein 1 (YAP1) as a tumor suppressor in FLT3-ITD+ AML. YAP1 inactivation conferred FLT3-ITD+ AML cell resistance to chemo- and targeted therapy. Mass spectrometric assay revealed that DNA damage repair gene poly (ADP-ribose) polymerase 1 (PARP1) might be the downstream of YAP1, and the pro-proliferative effect by YAP1 knockdown was partly reversed via PARP1 inhibitor. Importantly, histone deacetylase 10 (HDAC10) contributed to decreased YAP1 acetylation levels through histone H3 lysine 27 (H3K27) acetylation, leading to the reduced nuclear accumulation of YAP1. Selective HDAC10 inhibitor chidamide or HDAC10 knockdown activated YAP1, enhanced DNA damage, and significantly attenuated FLT3-ITD+ AML cell resistance. In addition, combination chidamide with FLT3 inhibitors or chemotherapy agents synergistically inhibited growth and increased apoptosis of FLT3-ITD+ AML cell lines and acquired resistant cells from the relapse FLT3-ITD+ AML patients. These findings demonstrate that the HDAC10-YAP1-PARP1 axis maintains FLT3-ITD+ AML cells and targeting this axis might improve clinical outcomes in FLT3-ITD+ AML patients.

Hypertension is a major risk factor leading to cardiovascular disease, and is frequently treated with angiotensin I-converting enzyme (ACE) inhibitory peptides. The objective of this study was to separate and identify an ACE-inhibitory peptide from goat milk casein hydrolysates, and to evaluate its potential for improving angiotensin II (Ang II)-mediated adverse effects on vascular smooth muscle cells (VSMCs). A novel ACE-inhibitory peptide with the highest activity from the goat milk casein hydrolysates as determined by four steps of RP-HPLC was purified and identified as Phe-Pro-Gln-Tyr-Leu-Gln-Tyr-Pro-Tyr (FPQYLQYPY). The results of inhibitory kinetics studies indicated that the peptide was a non-competitive inhibitor against ACE. Gastrointestinal digest in vitro analysis showed that the hydrolysate of FPQYLQYPY was still active after digestion with gastrointestinal proteases. Moreover, we found that the peptide could significantly inhibit the proliferation and migration of Ang II-stimulated VSMCs. Further transcriptomic analysis revealed that differentially expressed genes (DEGs) were enriched in the cardiovascular disease-related pathways, and that the peptide may have the ability to regulate vascular remodeling. Our findings indicate the potential anti-hypertensive effects of FPQYLQYPY, as well-implicate its role in regulating vascular dysfunction.

Aiming at the problems of poor classification effect, low accuracy, and long time in the current automatic classification methods of music genres, an automatic classification method of music genres based on deep belief network and sparse representation is proposed. The music signal is preprocessed by framing, pre-emphasis, and windowing, and the characteristic parameters of the music signal are extracted by Mel frequency cepstrum coefficient analysis. The restricted Boltzmann machine is trained layer by layer to obtain the connection weights between layers of the depth belief network model. According to the output classification, the connection weights in the model are fine-tuned by using the error back-propagation algorithm. Based on the deep belief network model after fine-tuning training, the structure of the music genre classification network model is designed. Combined with the classification algorithm of sparse representation, for the training samples of sparse representation music genre, the sparse solution is obtained by using the minimum norm, the sparse representation of test vector is calculated, the category of training samples is judged, and the automatic classification of music genre is realized. The experimental results show that the music genre automatic classification effect of the proposed method is better, the classification accuracy rate is higher, and the classification time can be effectively shortened.

Parkinson’s disease (PD) is one of the most common neurodegenerative disorders. However, its cellular and molecular mechanisms still wrap in the mist. This is partially caused by the absence of appropriate animal models mimicking sporadic PD that constitutes the majority of cases. Previously, we reported that a cysteine protease, asparagine endopeptidase (AEP), is activated in an age-dependent manner, and cleaves α-synuclein in the brain of sporadic PD patients. The AEP-derived α-synuclein 1-103 fragment is required for the pathogenesis of PD. Thus, we designed and characterized a novel transgenic mouse line expressing α-synuclein 1-103 (designated N103 mice). This model shows an abundant accumulation of pathological α-synuclein in the central nervous system, loss of dopaminergic neurons in the substantia nigra, and progressive striatal synaptic degeneration. The N103 mice also manifest age-dependent PD-like behavioral impairments. Notably, the mice show weight loss and constipation, which are the common non-motor symptoms in PD. The RNA-sequencing analysis found that the transcriptomics pattern was extensively altered in N103 mice. In conclusion, the N103 mouse line, as a brand-new tool, might provide new insights into PD research.

Parkinson's disease (PD) is one of the most common neurodegenerative diseases, which is characterized by the loss of dopaminergic neurons in the nigrostriatal pathway. Synaptic dysfunction impairs dopamine turnover and contributes to the degeneration of dopaminergic neurons. However, the molecular mechanisms underlying synaptic dysfunction and dopaminergic neuronal vulnerability in PD are not clear. Here, we report that synaptojanin 1 (SYNJ1), a polyphosphoinositide phosphatase concentrated at nerve terminals, is a substrate of a cysteine proteinase, asparagine endopeptidase (AEP). SYNJ1 is cleaved by the cysteine proteinase AEP at N599 in the brains of PD patients. AEP-mediated cleavage of SYNJ1 disrupts neuronal phosphoinositide homeostasis and causes synaptic dysfunction. Overexpression of the AEP-generated fragments of SYNJ1 triggers synaptic dysfunction and the degeneration of dopaminergic neurons, inducing motor defects in the α-synuclein transgenic mice. Blockage of AEP-mediated cleavage of SYJN1 alleviates the pathological and behavioral defects in a mouse model of PD. Our results demonstrate that the fragmentation of SYNJ1 by AEP mediates synaptic dysfunction and dopaminergic neuronal degeneration in PD.

Neurofibrillary tangles composed of hyperphosphorylated tau and synaptic dysfunction are characteristics of Alzheimer’s disease (AD). However, the underlying molecular mechanisms remain poorly understood. Here, we identified Amphiphysin I mediates both tau phosphorylation and synaptic dysfunction in AD. Amphiphysin I is cleaved by a cysteine proteinase asparagine endopeptidase (AEP) at N278 in the brains of AD patients. The amount of AEP-generated N-terminal fragment of Amphiphysin I (1-278) is increased with aging. Amphiphysin I (1-278) inhibits clathrin-mediated endocytosis and induces synaptic dysfunction. Furthermore, Amphiphysin I (1-278) binds p35 and promotes its transition to p25, thus activates CDK5 and enhances tau hyperphosphorylation. Overexpression of Amphiphysin I (1-278) in the hippocampus of Tau P301S mice induces synaptic dysfunction, tau hyperphosphorylation, and cognitive deficits. However, overexpression of the N278A mutant Amphiphysin I, which resists the AEP-mediated cleavage, alleviates the pathological and behavioral defects. These findings suggest a mechanism of tau hyperphosphorylation and synaptic dysfunction in AD.

Chironomidae is the most ecologically diverse insects in aquatic and semi-aquatic habitats. Propsilocerus akamusi (Tokunaga) is a dominant and ubiquitous chironomid species in Eastern Asia and its morphologically unique larvae are also considered as indicator organisms to detect water contamination, potential toxicity and waterborne pathogens. Since few studies to date have focused on the olfactory system of P. akamusi, our study aims to elucidate the potential functions of chemosensory genes in P. akamusi. In our study, we found that although signals released from male groups might attract female swarmers, it was a completely male-dominated mating process. Sequencing the transcriptome of P. akamusi on an Illumina HiSeq platform generated 4.42, 4.46 and 4.53 Gb of clean reads for heads, legs, and antennae, respectively. 27,609 unigenes, 20,379 coding sequences (CDSs), and 8,073 simple sequence repeats were finally obtained. The gene-level differential expression analysis demonstrated variants among three different tissues, including 2,019 genes specifically expressed in heads, 1,540 genes in legs, and 2,071 genes in antennae. Additionally, we identified an assortment of putative olfactory genes consisting of 34 odorant binding proteins, 17 odorant receptors, 32 gustatory receptors, 22 ionotropic receptors, six chemosensory proteins as well as 3 sensory neuron membrane proteins; their relative abundances in the above three tissues were also determined by RT-qPCR. Our finding could allow a more plausible understanding of certain olfaction-mediated behaviors in groups of this macroinvertebrate.

Diet is believed to play a major role in maternal recovery, postpartum weight retention (PPWR) is one of the challenges for Chinese women. However, the association between puerperal women's diet and PPWR remained unclear and complicated in China. The study assessed the dietary quality of puerperal women using adjusted Chinese Dietary Balance Index-16 (DBI-16) and explored its associations with PPWR. Participants were enrolled in the Mother-Infant Cohort Study of China. Dietary intake and demographic characteristics were obtained by a semi-quantitative food frequency questionnaire and a self-designed questionnaire at 0-3 months postpartum. PPWR was calculated by the weight difference at 0-3months and 6-8months postpartum minus pre-pregnancy weight. Dietary quality was assessed using adjusted DBI-16. 316 puerperal women were enrolled. According to adjusted DBI-16, 84.8% of participants had an insufficient dietary intake (vegetables 84.8%, fruits 91.8%, dairy 87.3%, soybean 61.4% and aquatic foods 79.4%, respectively), 67.1% had an excessive intake (cereals 60%, meat 57.3% and eggs 64.9%, respectively), 98.4% had an imbalanced diet consumption. PPWR at 0-3, and 6-8 months were 6.0 (±5.1) kg and 5.2 (±7.7) kg, and the percentage of PPWR (≥5kg) were 63.0% and 52.8% respectively. Multivariable linear regression showed the intake of fish and shrimp at 0-3 months postpartum was negatively associated with PPWR at 6-8 months (β = -0.114, SE = 0.279, p < 0.05). The diet quality of Chinese puerperal women was unreasonable and imbalanced. Fish intake tended to be a favorable factor for postpartum weight loss.

BACKGROUND: 2'-Fucosyllactose, a representative oligosaccharide in human milk, is an emerging and promising food and pharmaceutical ingredient due to its powerful health benefits, such as participating in immune regulation, regulation of intestinal flora, etc. To enable economically viable production of 2'-fucosyllactose, different biosynthesis strategies using precursors and pathway enzymes have been developed. The α-1,2-fucosyltransferases are an essential part involved in these strategies, but their strict substrate selectivity and unsatisfactory substrate tolerance are one of the key roadblocks limiting biosynthesis. RESULTS: To tackle this issue, a semi-rational manipulation combining computer-aided designing and screening with biochemical experiments were adopted. The mutant had a 100-fold increase in catalytic efficiency compared to the wild-type. The highest 2'-fucosyllactose yield was up to 0.65 mol mol-1 lactose with a productivity of 2.56 g mL-1 h-1 performed by enzymatic catalysis in vitro. Further analysis revealed that the interactions between the mutant and substrates were reduced. The crucial contributions of wild-type and mutant to substrate recognition ability were closely related to their distinct phylotypes in terms of amino acid preference. CONCLUSION: It is envisioned that the engineered α-1,2-fucosyltransferase could be harnessed to relieve constraints imposed on the bioproduction of 2'-fucosyllactose and lay a theoretical foundation for elucidating the substrate recognition mechanisms of fucosyltransferases. [ABSTRACT FROM AUTHOR]

Abstract Tertiary lymphoid structures (TLSs) play a crucial role in determining prognosis and response to immunotherapy in several solid malignancies. Nevertheless, the effect of TLS-associated gene signature based on The Cancer Genome Atlas (TCGA) cohort in patients with breast cancer (BRCA) remains controversial. Based on TCGA-BRCA dataset (n = 866), 9-gene was identified to construct an TLS signature and further analyzed its prognostic value. Then, we explored the relationship of this TLS signature with molecular subtype, immune microenvironment, tumor mutational burden (TMB). High-TLS signature patients had a better overall survival (OS) than low-TLS signature patients, consistent with the results in the METABRIC cohort. Multivariate analysis revealed that TLS signature remained an independent prognostic indicator for OS. In addition, we established a nomogram with the integration of TLS signature and other independent variables to predict individual risk of death. The comprehensive results showed that patients with high TLS signature benefit from immunotherapy; the signature was also correlated with inhibition of cell proliferation pathways, low TP53 mutation rate, high infiltration of B cells, CD8 + T cells, CD4 + T cells, and M1 macrophages. Therefore, TLS signature is a promising biomarker to distinguish the prognosis and immune microenvironment in BRCA.

Objectives] To establish a quality standard method for detecting rutin in leaves of Thespesia populnea. [Methods] The leaves of T. populnea as a reagent, the rutin in the leaves of ! populnea was extracted by alcohol extraction, and quantitatively analyzed by high performance liquid chromatography $ HPLC). [ Results] In the range of 0. 21 -3.36 xg, the peak area A of rutin in the leaves of ! populnea had a good linear relationship with its injection volume m. A = 1 561.6 m - 6. 893, and the correlation coefficient r = 1. 000 0. The method was applied to the determination of rutin ethyl acetate extract in the leaves of T. populnea, the average recovery rate was 101.75%, and the RRD was 1.32%. [ Conclusions] This method is simple and feasible, the results are accurate, the repeatability is good, and the separation efect is good. It is expected to provide a scientific idea for the determination of rutin in the leaves of T. populnea. [ABSTRACT FROM AUTHOR]

Townscape research in the context of urban morphology research is a new direction. To understand the scope and need of research, first, you need to answer the question of what townscape is and how it can be understood in the context of research of various directions, what is the object being studied. It is important to understand why there was a need for research in such a direction and what influence it had on urban planning and design. The article aims to name the concept of townscape in the eyes of different researchers, to describe the possible ways of understanding and researching the townscape, to reveal the origin and need of townscape research in area of today’s urban design. The main goal of the article is to refine the definition of the concept of townscape. Article in Lithuanian. Miestovaizdis: samprata ir tyrimų kilmė Santrauka Miestovaizdžio tyrimai miesto morfologijos tyrimų kontekste yra palyginti nauja kryptis. Norint suvokti tyrimų apimtį ir poreikį, pirmiausia reikia atsakyti į klausimą, kas yra miestovaizdis ir kaip jis gali būti suprantamas įvairios krypties tyrimų kontekste, koks yra tiriamas objektas. Svarbu suvokti, kodėl atsirado poreikis tokios krypties tyrimams ir kokią įtaką tai turėjo miestų planavimui ir projektavimui. Straipsnyje siekiama įvardinti miestovaizdžio sampratą skirtingų tyrėjų akimis, aprašyti galimus miestovaizdžio suvokimo ir tyrimų būdus, atskleisti miestovaizdžio tyrimų kilmę ir poreikį šių dienų miestų projektavimo plotmėje. Pagrindinis straipsnio tikslas – išsigryninti miestovaizdžio sąvokos apibrėžimą. Reikšminiai žodžiai: miestas, miestovaizdis, morfologija, sąvoka, urbanistinė struktūra, urbanistinis projektavimas.

Abstract Stability of nitrogen cycle is a key indicator to aquatic health. In recent years, water and sediment inflows to the Three Gorges Reservoir (TGR) have changed significantly. To reveal the effects of such dramatic hydrological changes on aquatic nitrogen cycle, this paper at first analyzed the changing trends of water and suspended sediment discharges of TGR based on dynamic harmonic regression, and found that the intra‐year distribution of water flow was significantly homogenized between flood and dry seasons, with the seasonal variations narrowed by 43.5%–69.9% during 2007–2016, while sediment concentration sharply dropped (the non‐periodic term decreased by 1.48%–2.07%/month). Modified with the effects of sediment concentration variations on nitrification/denitrification rates, the proposed numerical model surprisingly showed that ammonia nitrogen and total nitrogen concentrations in TGR were insensitive to either water flow homogenization or sediment reduction, implying relative stability of microbial community related to nitrogen cycle, which is a positive sign for aquatic health. However, N2 emission varied more violently. The variation range of nitrogen gas (N2) emitted from TGR enlarged by 30% with the homogenization of water inflow from 2010 to 2016, while the annual total N2 emission decreased by 7% due to the reduction of sediment concentration, indicating quick response and strong adaption of the microbial N2 producing process to the environmental changes of TGR, which is beneficial for maintaining ecological functions related to nitrogen cycling. This work helps understanding nitrogen cycle of reservoirs experiencing dramatic changes in water and sediment inflows.

Summary: Background: Early death after cancer surgery is higher in low-income and middle-income countries (LMICs) compared with in high-income countries, yet the impact of facility characteristics on early postoperative outcomes is unknown. The aim of this study was to examine the association between hospital infrastructure, resource availability, and processes on early outcomes after cancer surgery worldwide. Methods: A multimethods analysis was performed as part of the GlobalSurg 3 study—a multicentre, international, prospective cohort study of patients who had surgery for breast, colorectal, or gastric cancer. The primary outcomes were 30-day mortality and 30-day major complication rates. Potentially beneficial hospital facilities were identified by variable selection to select those associated with 30-day mortality. Adjusted outcomes were determined using generalised estimating equations to account for patient characteristics and country-income group, with population stratification by hospital. Findings: Between April 1, 2018, and April 23, 2019, facility-level data were collected for 9685 patients across 238 hospitals in 66 countries (91 hospitals in 20 high-income countries; 57 hospitals in 19 upper-middle-income countries; and 90 hospitals in 27 low-income to lower-middle-income countries). The availability of five hospital facilities was inversely associated with mortality: ultrasound, CT scanner, critical care unit, opioid analgesia, and oncologist. After adjustment for case-mix and country income group, hospitals with three or fewer of these facilities (62 hospitals, 1294 patients) had higher mortality compared with those with four or five (adjusted odds ratio [OR] 3·85 [95% CI 2·58–5·75]; p

PurposeAs a novel small-molecule vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor (VEGFR2-TKI), Methylsulfonic apatinib (apatinib) exhibits a specific antitumor effect in various solid tumors via inhibition of angiogenesis. The present study was performed to evaluate the clinical efficacy and safety of apatinib in the treatment of advanced cholangiocarcinoma after failed gemcitabine-based chemotherapy.Patients and MethodsThis was a prospective open-label phase II trial (NCT03521219). A total of 32 patients, in whom gemcitabine-based first-line chemotherapy for advanced intrahepatic cholangiocarcinoma had failed, were consecutively enrolled in a prospective, open, exploratory, and single-center clinical trial from November 2017 to November 2018. They were treated with apatinib mesylate second-line monotherapy (orally, 500 mg per day for a cycle of 28 days) until progressive disease or unacceptable toxicity. Using Response Evaluation Criteria in Solid Tumor version 1.1 (RECIST 1.1) and the Common Terminology Criteria for Adverse Events version 4.0 (NCI-CTCAE 4.0), the efficacy and adverse were evaluated, respectively. Kaplan-Meier method was used for survival analysis.ResultsTwenty-six patients were enrolled in full analysis set. At the end of follow-up, two patients were lost to follow-up, 24 of 26 patients in FAS were included in efficacy analyses. For the efficacy analysis set, the objective response rate (ORR) was 20.8% [95% confidence interval (CI): 9.24–40.47%] and the disease control rate (DCR) was 62.5% (95% CI: 112.86–387.14 days). One patient (4%) showed complete response (CR), 4 patients (17%) showed partial response (PR), 10 patients (41.7%) stable disease (SD), and 9 patients (37.5%) had progressive disease (PD). Meanwhile, apatinib therapy achieved the median progression-free survival PFS was 95 days (95% CI: 79.70–154.34 days), and the median OS was 250 days (95% CI: 112.86–387.14 days). Furthermore, univariate analysis revealed that age and tumor’s anatomic location significantly affected PFS (P < 0.05). The most common clinically adverse events (AEs) included myelosuppression (69.2%), hypertension (57.7%), proteinuria (46.2%). The AEs were mild, mainly in grade 1 or 2, and no toxicity-induced death occurred.ConclusionApatinib monotherapy is an effective and promising regimen for treating patients with advanced cholangiocarcinoma who experienced failure of gemcitabine-based chemotherapy.

Background: Data regarding the real-life predictors of low disease activity (LDA) in rheumatoid arthritis (RA) patients are limited. Our aim was to evaluate the rate and predictors of LDA and treatment patterns in RA. Methods: This was a multicenter, prospective, RA cohort study where patients were evaluated in two different time points approximately 12 months apart. Statistical analysis was performed in order to identify predictors of LDA while patterns of disease-modifying anti-rheumatic drug [DMARDs; conventional synthetic (csDMARD) or biologic (bDMARD)] and glucocorticoid (GC) use were also recorded. Results: The total number of patients included was 1317 (79% females, mean age: 62.9 years, mean disease duration: 10.3 years). After 1 year, 57% had achieved LDA (DAS28ESR3.2), 21% initiated (among csDMARDs users) and 22% switched (among bDMARDs users) their bDMARDs. Conclusion: In a real-life RA cohort, during 1 year of follow-up, 43% of patients do not reach treatment targets while only ~20% of those with active RA started or switched their bDMARDs. Male sex, younger age, lower HAQ, body mass index and co-morbidity index were independent factors associated with LDA while use of GCs or ⩾2 bDMARDs were negative predictors.

Previous studies have shown an anticancer effect of vitamin D, but the mechanisms underlying this action have not been fully explored. Here we show that 1,25-dihydroxyvitamin D3 (VD3, the active form of vitamin D) significantly promoted apoptosis in the undifferentiated gastric cancer cell line HGC-27, and this was accompanied by a concurrent increase in phosphatase and tensin homolog deleted on chromosome 10 (PTEN) expression on VD3 treatment. In contrast, knockdown of PTEN expression by stable transfection of PTEN small interfering RNA greatly decreased the apoptosis rate. We further demonstrated that VD3 induced PTEN expression through vitamin D receptor. In addition, our evidence showed that vitamin D receptor, Egr-1 and p300 induced PTEN expression in a synergistic fashion. Furthermore, we found that the histone deacetylase inhibitors trichostatin A and sodium butyrate and the methylation inhibitor 5-aza-2′-deoxycytidine played important roles in vitamin D-induced apoptosis through PTEN upregulation. The data presented in this article suggest potential benefits of vitamin D in gastric cancer therapies in association with the use of trichostatin A/sodium butyrate and 5-aza-2′-deoxycytidine. Structured digital abstract • , , : P300 (uniprotkb: ) physically interacts ( ) with VDR (uniprotkb: ) and EGR1 (uniprotkb: ) by anti bait coimmunoprecipitation ( ) [ABSTRACT FROM AUTHOR]

Abstract  p16INK4a plays a key role in control of cell cycle progression by negatively regulating the CDK4/6 activity. This study establishes that the p16INK4a minimal promoter region required for the transcription factor Sp1 function is mapped at 62 bp upstream of the translation initiation codon. This region is GC-rich and shown to interact specifically with Sp1. siRNA-induced Sp1 silencing resulted in the inhibition of the p16INK4a minimal promoter activity. Additionally, by using a promoter sequence-directed siRNA method, we demonstrate that the histone H3 at the GC-rich region in the minimal promoter of p16INK4a is hypermethylated, with a concurrent reduction of both the activity of p16INK4a promoter and the level of endogenous p16INK4a mRNA. Moreover, we show that the specific mutation of the GC-rich region of the minimal promoter resulted in the complete loss of its regulatory activities. We conclude that the region spanning −62 to +1 bp of p16INK4a promoter plays a role in p16INK4a transcription regulation. [ABSTRACT FROM AUTHOR]

Background. Desmoid type fibromatosis of the breast is a rare fibroblastic proliferative disease. It may be sporadic or associated with trauma, Gardner’s syndrome, etc. Desmoid tumour of the breast is a benign, locally aggressive disease. However, it does not metastasize. Case report. We report a case of a 65-year-old woman with right breast desmoid type fibromatosis. Conclusions. Diagnosis of breast desmoid tumour is difficult: clinically and radiologically it may mimic carcinoma. Definitive diagnosis is proved just by histopathological examination results. First choice treatment of breast fibromatosis is a radical surgical excision.

Organic products generated from waste activated sludge hydrolysis and fermentation process could be used as supplementary carbon source for enhanced biological nutrient removal. However, accompanied with organics production, large amount of ammonia nitrogen (NH4+-N) and soluble orthophosphorus (SOP) released, which would be negative to the reutilization of sludge carbon source. In this study, based on wasted activated sludge thermal-alkaline and short-cut fermentation process, optimal conditions for NH4+-N and SOP removal condition, and sludge carbon source recovery from short-cut fermentation liquid have been investigated systematically using response surface method. Results showed that, the removal rate of NH4+-N and SOP were 72.27% and 85.98% respectively, and the SCOD recovery rate was 80.74%.

In order to control the continued development of high-rise buildings and their irreversible visual impact on the overall silhouette of the city, the great cities of the world introduced new methodological principles to city’s spatial development models. These methodologies and spatial planning guidelines are focused not only on the controlled development of high-rise buildings, but on the spatial modelling of the whole city by defining main development criteria and estimating possible consequences. Vilnius city is no exception, however the re-establishment of independence of Lithuania caused uncontrolled urbanization process, so most of the city development regulations emerged as a consequence of unmanaged processes of investors’ expectations legalization. The importance of consistent urban fabric as well as conservation and representation of city’s most important objects gained attention only when an actual threat of overshadowing them with new architecture along with unmanaged urbanization in the city center or urban sprawl at suburbia, caused by land-use projects, had emerged. Current Vilnius’ spatial planning documents clearly define urban structure and key development principles, however the definitions are relatively abstract, causing uniform building coverage requirements for territories with distinct qualities and simplifying planar designs which do not meet quality standards. The overall quality of urban architecture is not regulated. The article deals with current spatial modeling methods, their individual parts, principles, the criteria for quality assessment and their applicability in Vilnius. The text contains an outline of possible building coverage regulations and impact assessment criteria for new development. The article contains a compendium of requirements for high-quality spatial planning and building design. Santrauka Didieji pasaulio miestai, norėdami suvaldyti XXI a. prasidėjusią ir iki šiol besitęsiančią aukštybinių pastatų plėtrą, kuri sukėlė negrįžtamą vizualinį poveikį bendram miesto siluetui, pradėjo taikyti naujausius erdvinės plėtros modeliavimo metodologinius principus miesto erdvinei plėtrai formuoti. Šios metodologijos, sukurtos planavimo gairės yra orientuotos ne tik į aukštybinių pastatų plėtros suvaldymą mieste, bet į viso miesto erdvinį modeliavimą numatant pagrindinius plėtros kriterijus ir įvertinant galimas pasekmes. Vilniaus miestas šiuo atveju nėra išimtis, tačiau atkūrus nepriklausomybę, prasidėjus nevaldomiems urbanizacijos procesams dauguma miesto plėtrą reglamentuojančių dokumentų atsirado kaip nesuvaldomų procesų įteisinant investuotojų lūkesčius pasekmė. Apie miesto kaip vientiso urbanistinio audinio formavimą, jo svarbiausių, vertingiausių objektų išsaugojimą ir reprezentavimą buvo pradėta galvoti tik tada, kai atsirado reali jų nustelbimo nauja architektūra grėsmė, urbanizacijos procesai ne tik miesto centre, bet ir jo pakraščiuose tapo nevaldomi, nulemti žemėtvarkos projektų. Dabartiniai Vilniaus mieste galiojantys teritorijų planavimo dokumentai, nors ir aiškiai apibrėžia miesto struktūros ypatumus ir galimus statybos principus, tačiau yra palyginti abstraktūs, galutiniai reglamentai niveliuoja užstatymą skirtingus požymius turinčiose teritorijose, pateikiami supaprastinti planiniai sprendiniai, kurie negarantuoja kokybiško galutinio rezultato. Urbanistinė architektūrinė kokybė nėra reglamentuojama. Straipsnyje nagrinėjamos esamų erdvinio modeliavimo metodologijų, atskirų jų dalių, principų, vertinimo kriterijų taikymo galimybės Vilniaus mieste. Įvardijama, kokiame miesto sistemos planavimo etape šios metodikos ir miesto planavimo principai, atlikti tyrimai gali būti taikomi praktiškai. Taip pat įvardijami galimi užstatymo rodiklių reglamentavimo bei pasekmių vertinimo kriterijai naujai plėtrai. Pateikiamas kokybiško teritorijų planavimo ir pastatų projektavimo reikalavimų sąvadas. Reikšminiai žodžiai: sistema, praktinis taikymas, miestas, erdvinis miesto valdymas, urbanistinė struktūra, morfotipas, miestovaizdis, kvartalas, pasekmių vertinimas, modeliavimas, metodologija.

Objective To explore the effect of Morinda citrifolia juice (MCJ) combined with ethylene diamine tetraacetic acid (EDTA) on premolar bonding strength and nanoleakage and compare the results with those of the most commonly used root canal irrigation solution, sodium hypochlorite (NaClO), to provide a reference for clinical application. Methods This study was approved by the ethics review committee. Sixty-three human premolars extracted for orthodontic treatment were randomly divided into a control group (distilled water group) and 6 experimental groups according to the different rinsing solutions used after the surface enamel was removed. The experimental groups included Group A (2.5% NaClO), Group B (5.25% NaClO), Group C (6% MCJ), Group D (2.5% NaClO-17% EDTA), Group E (5.25% NaClO-17% EDTA), and Group F (6% MCJ-17% EDTA) (n = 9). After soaking in the corresponding rinsing solution for 20 minutes, they were layered and stacked on their surfaces to form 4 mm × 4 mm × 3 mm Z350 resin blocks. Six samples from each group were cut into 1 mm × 1 mm × 8 mm specimen strips for microtensile bonding strength testing. The fracture type was determined under a stereomicroscope, and the remaining 3 samples from each group were aged and cut into 1 mm thick slices for interface nanoleakage testing and scanning electron microscopy observation of the resin dentin bonding interface. Results There were significant differences in the microtensile bonding strength among the groups (PP

High rise buildings is the phenomenon of XXI century, the expression of city’s economic and political power. This is the reflection of contemporary, modern and attractive city. Very often high rise buildings, who are characterized by a unique morphology, the parameters of high, density and intensity, are built near the historic center areas and cause irreversible visual impact on the historic sites, fundamentally altering the silhouette of the city. As a result, new problems and challenges appear. In this article the evolution of high rise buildings according to London, Jerusalem, Ottawa, Vilnius cities examples is analysed, the latest methodological principles which are applicable to control the development of high-rise buildings in the central parts of the city, while providing preservation and representation of cultural heritage are discussed. The latest computer technologies which are applied in urban regulations are presented. In case of Lithuania, high-rise building spatial development, general, spatial planning documents, urban design concepts, and monitoring of virtual city panoramas are reviewed. Comparative analysis in order to find out the essential methodological differences between cities regulation systems is done. Santrauka Aukštybiniai pastatai – XXI a. fenomenas, miestų ekonominės, politinės galios išraiška. Tai šiuolaikinio, modernaus ir patrauklaus miesto atspindys. Labai dažnai aukštybinis užstatymas, pasižymintis savita morfologija, aukščio ir tūrio parametrais, dideliu užstatymo tankiu ir intensyvumu, atsiranda istorinių centrų prieigose, sukeldamas negrįžtamą vizualinį poveikį istoriniam paveldui, iš esmės pakeisdamas miesto siluetą. Dėl to atsiranda naujų problemų ir uždavinių. Straipsnyje nagrinėjama aukštybinių pastatų reglamentavimo evoliucija pagal Londono, Jeruzalės, Otavos ir Vilniaus miestų pavyzdį. Norint suvaldyti aukštybinių pastatų plėtrą šių miestų centrinėse dalyse, taikomi naujausi metodologiniai principai, numatant išsaugoti ir reprezentuoti ir kultūros paveldo objektus. Aptariamos naujausių kompiuterinių technologijų taikymo galimybės reglamentuojant miestus. Lietuvos atveju apžvelgiama Vilniaus miesto aukštybinių pastatų statybos raida, bendrojo, specialiojo planavimo dokumentai, parengtos koncepcijos, virtualių miesto panoramų monitoringas. Atliekama lyginamoji analizė, norint išsiaiškinti esminius metodologijų ir reglamentavimo skirtumus miestuose. Reikšminiai žodžiai: aukštybinis užstatymas, užstatymo morfotipas, istorinis paveldas, miesto panoramos, vizualinė apsauga, metodologija, erdvinis miesto valdymas, reglamentas.

Įžanga Videotorakoskopinė chirurgija (VATS) visame pasaulyje pirmuosius žingsnius žengė daugiau nei prieš dvidešimt metų. Įprastinė trijų angų VATS buvo patobulinta iki vienos angos VATS. Pacientai, kuriems atliktos minimaliai invazinės operacijos, jaučia mažesnį pooperacinį skausmą, greičiau sveiksta. Be to, didelės torakoskopinės plaučių rezekcijos gali būti atliekamos ir neintubuotiems pacientams. Klinikinis atvejis Lietuvos sveikatos mokslų universiteto ligoninėje pirmą kartą Lietuvos istorijoje sėkmingai atlikta vienos angos videotorakoskopinė kairė viršutinė lobektomija 68 metų pacientui, sirgusiam nesmulkialąsteliniu plaučių vėžiu. Išvados Neintubuotam pacientui atlikta vienos angos VATS lobektomija, esant vėžio pažeistai plaučio skilčiai, yra saugi ir efektyvi operacija.

Įvadas Viena iš retų elektrokardiostimuliatoriaus ar defibriliatoriaus implantacijos komplikacijų yra širdies perforacija. Jos klinikinės išraiškos pasižymi didele įvairove ir gali sukelti daug diagnostikos sunkumų. Klinikinis atvejis Į mūsų ligoninę dėl sinusinio mazgo silpnumo sindromo hospitalizuotas 80 metų ligonis. Jam implantuotas dviejų kamerų ilgalaikis kardiostimuliatorius. Procedūros komplikacijos – širdies perforacija, hemoperikardiumas ir dešinės pusės hemoto­raksas. Po procedūros praėjus kelioms valandoms, ligonis pasijuto blogai, tačiau tiksli širdies perforacijos diagnozė nustatyta tik penktą dieną po kardiostimuliatoriaus implantavimo, kai atlikta krūtinės ląstos kompiuterinė tomografija. Tuomet elek­trofiziologas, padedamas chirurgų, kontroliuojant procedūrą torakoskopu, pašalino migravusį elektrokardiostimuliatoriaus elektrodą. Kitą dieną ligoniui įdėtas naujas elektrodas. Praėjus šešiolikai dienų po elektrokardiostimuliatoriaus implantavimo, vyras išrašytas iš ligoninės. Išvados Literatūroje minima, kad dauguma migravusių elektrodų gali būti paprastai ištraukti kontroliuojant procedūrą rentgenu ar stebint echokardiografu operacinėje, kartu esant pasirengusiai chirurgų komandai. Mes sėkmingai pašalinome elektrodą kontroliuodami procedūrą torakoskopu.

Parkinson's disease (PD) is characterized by the pathologic aggregation and prion-like propagation of a-synuclein (a-syn). Emerging evidence shows that fungal infections increase the incidence of PD. However, the molecular mechanisms by which fungi promote the onset of PD are poorly understood. Here, we show that nasal infection with Saccharomyces cerevisiae (S. cerevisiae) in a-syn A53T transgenic mice accelerates the aggregation of a-syn. Furthermore, we found that Sup35, a prion protein from S. cerevisiae, is the key factor initiating a-syn pathology induced by S. cerevisiae. Sup35 interacts with a-syn and accelerates its aggregation in vitro. Notably, injection of Sup35 fibrils into the striatum of wild-type mice led to a-syn pathology and PD-like motor impairment. The Sup35-seeded a-syn fibrils showed enhanced seeding activity and neurotoxicity compared with pure a-syn fibrils in vitro and in vivo. Together, these observations indicate that the yeast prion protein Sup35 initiates a-syn pathology in PD. [ABSTRACT FROM AUTHOR]

Cell senescence, an irreversible cell cycle arrest, reflects a safeguard program that limits the capacity of uncontrolled cell proliferation. Treatment of tumor cells with certain chemotherapeutic agents activates premature senescence to decrease the tumorigenecity. Here we show that sublethal concentrations of adriamycin could induce premature senescence in lung cancer cells. Adriamycin treatment resulted in the up-regulation of BMP4, which is underexpressed in NSCLC (non-small cell lung cancers). Moreover, the BMP4-Smad pathway played a key role in mediating adriamycin-induced senescence. Overexpression of BMP4 was able to induce premature senescence in lung cancer cells and this process required the participation of cyclin/cyclin-dependent kinase (cdk) inhibitors p16INK4a and p21WAF1/cip1. We also show that increases of p16INK4a and p21WAF1/cip1 expression in response to BMP4 were mediated by the Smad signaling pathway. Furthermore, our data revealed that p300 was recruited to P16INK4a and P21WAF1/cip1 promoters by Smad1/5/8 to induce the hyperacetylation of histones H3 and H4 at the promoters. The present study provides useful clues to the evaluation of the potentiality of BMP4 as a responsive molecular target for cancer chemotherapy. [ABSTRACT FROM AUTHOR]