The diabetes mellitus multimorbidity network in hospitalized patients over 50 years of age in China: data mining of medical records.

OBJECTIVE: Many diabetes mellitus (DM) patients suffer from multimorbidity. Understanding the DM multimorbidity network should be given priority. The purpose of this study is characterize the DM multimorbidity network in people over 50 years. METHODS: Data on 75 non-communicable diseases (NCDs) were extracted from electronic medical records of 309,843 hospitalized patients older than 50 years who had at least one NCD. The association rules analysis was used as a novel classification method and combined with the Chi-square tests to identify associations between NCDs and DM. RESULT: A total of 12 NCDs were closely related to DM, {cholelithiasis, DM} was an unexpected combination. {dyslipidemia, DM} and {gout, DM} had the largest lift in the male and female groups, respectively. The negative related group included 7 NCDs. There were 9 NCDs included in the strong association rules. Most combinations were different by age and sex. In males, the strongest rule was {peripheral vascular disease (PVD), dyslipidemia, DM}, while {hypertension, dyslipidemia, chronic liver disease (CLD), DM} was the strongest in females. In patients younger than 70 years, hypertension, CLD, and dyslipidemia were the most dominant NCDs in the DM multimorbidity network. In patients 70 years or older, chronic kidney disease (CKD), CVD, CHD, and heart disease (HD) frequently co-occurred with DM. CONCLUSION: Future primary healthcare policies for DM should be formulated based on age and sex. In patients younger than 70 years, more attention to hypertension, CLD, and dyslipidemia is required, while attention to CKD, CVD, CHD and HD is needed in patients older than 70 years.

Selectivity Mechanism of Pyrrolopyridone Analogues Targeting Bromodomain 2 of Bromodomain-Containing Protein 4 from Molecular Dynamics Simulations.

Bromodomain and extra-terminal domain (BET) proteins play an important role in epigenetic regulation and are linked to several diseases; therefore, they are interesting targets. BET has two bromodomains: bromodomain 1 (BD1) and BD2. Selective targeting of BD1 or BD2 may produce different activities and greater effects than pan-BD inhibitors. However, the selective mechanism of the specific core must be studied at the atomic level. This study determined the effectiveness of pyrrolopyridone analogues to selectively inhibit BD2 using a pan-BD inhibitor (ABBV-075) and a selective-BD2 inhibitor (ABBV-744). Molecular dynamics simulations and calculations of binding free energies were used to systematically study the selectivity of BD2 inhibition by the pyrrolopyridone analogues. Overall, the pyrrolopyridone analogue inhibitors targeting BD2 interacted mainly with the following amino acid pairs between bromodomain-containing protein 4 (BRD4)-BD1 and BRD4-BD2 complexes: I146/V439, N140/N433, D144/H437, P82/P375, V87/V380, D88/D381, and Y139/Y432. The pyrrolopyridone analogues targeting BRD4-BD2 were divided into five regions based on selectivity mechanism. These results suggest that the R3 and R5 regions of pyrrolopyridone analogues can be modified to improve the selectivity between BRD4-BD1 and BRD4-BD2. The selectivity of BD2 inhibition by pyrrolopyridone analogues can be used to design novel BD2 inhibitors based on a pyrrolopyridone core.

Cholesterol alone or in combination is associated with frailty among community-dwelling older adults: A cross-sectional study.

BACKGROUND: Biological markers contribute to the precise intervention across the continuum of frailty severity. Few studies have explored the advantages of biological markers collected as part of primary care data among community-dwelling older adult population and controversy remains regarding the classic biological markers for frailty. METHODS: We recruited a total of 8791 adults with a mean age of 71.95 years who met the inclusion and exclusion criteria in Guancheng District and Dalang Town, Dongguan, China. Frailty was assessed by a Chinese frailty evaluation scale. Frailty status was classified with 33-item modified frailty index and latent class analysis was applied to explore the latent classes (subtypes) of frailty. We measured biological markers on blood samples collected. We identify association between specific biological markers or patterns and frailty by logistic regression and association rule mining (ARM) based on the Apriori algorithm. RESULTS: Multivariable analysis of our data showed that an elevated white blood cell (WBC) count and high cholesterol (CHOL) level were associated with pre-frailty (adjusted odds ratio [aOR] = 1.231, 95 % confidence interval [CI] = 1.009-1.501; aOR = 0.703, 95 % CI = 0.623-0.793) and frailty (aOR = 1.500, 95 % CI = 1.130-1.993; aOR = 0.561, 95 % CI = 0.461-0.684) compared with the normal groups. Importantly, significantly high level of CHOL was associated with a lower risk of four frailty subtypes compared with relatively healthy participants with the most power of association in the multi-frail group (aOR = 0.182, 95 % CI = 0.086-0.386). Based on ARM technique to develop correlation analysis to identify important high-risk clusters among older adult transitions from non-frail to frailty, patterns for normal level of CHOL co-occurred with an elevated creatinine (CREA) level have a significant association with the risk of frailty (aOR = 7.787, 95 % CI = 1.978-30.648) after adjusting for targeted confounders. CONCLUSIONS: Our study highlights the correlation between classic biological markers, especially CHOL and frailty status and subtypes among community-dwelling older adult, in the primary care setting. Further large-scale prospective studies are still needed to confirm the role of classic biological markers in frailty.

Identification of abemaciclib derivatives targeting cyclin-dependent kinase 4 and 6 using molecular dynamics, binding free energy calculation, synthesis, and pharmacological evaluation.

CDK4/6 plays a crucial role in various cancers and is an effective anticancer drug target. However, the gap between clinical requirements and approved CDK4/6 drugs is unresolved. Thus, there is an urgent need to develop selective and oral CDK4/6 inhibitors, particularly for monotherapy. Here, we studied the interaction between abemaciclib and human CDK6 using molecular dynamics simulations, binding free energy calculations, and energy decomposition. V101 and H100 formed stable hydrogen bonds with the amine-pyrimidine group, and K43 interacted with the imidazole ring via an unstable hydrogen bond. Meanwhile, I19, V27, A41, and L152 interacted with abemaciclib through π-alkyl interactions. Based on the binding model, abemaciclib was divided into four regions. With one region modification, 43 compounds were designed and evaluated using molecular docking. From each region, three favorable groups were selected and combined with each other to obtain 81 compounds. Among them, C2231-A, which was obtained by removing the methylene group from C2231, showed better inhibition than C2231. Kinase profiling revealed that C2231-A showed inhibitory activity similar to that of abemaciclib; additionally, C2231-A inhibited the growth of MDA-MB-231 cells to a greater extent than did abemaciclib. Based on molecular dynamics simulation, C2231-A was identified as a promising candidate compound with considerable inhibitory effects on human breast cancer cell lines.

Impact of Cavitation Jet on the Structural, Emulsifying Features and Interfacial Features of Soluble Soybean Protein Oxidized Aggregates.

A cavitation jet can enhance food proteins' functionalities by regulating solvable oxidized soybean protein accumulates (SOSPI). We investigated the impacts of cavitation jet treatment on the emulsifying, structural and interfacial features of soluble soybean protein oxidation accumulate. Findings have shown that radicals in an oxidative environment not only induce proteins to form insoluble oxidative aggregates with a large particle size and high molecular weight, but also attack the protein side chains to form soluble small molecular weight protein aggregates. Emulsion prepared by SOSPI shows worse interface properties than OSPI. A cavitation jet at a short treating time (<6 min) has been shown to break the core aggregation skeleton of soybean protein insoluble aggregates, and insoluble aggregates into soluble aggregates resulting in an increase of emulsion activity (EAI) and constancy (ESI), and a decrease of interfacial tension from 25.15 to 20.19 mN/m. However, a cavitation jet at a long treating time (>6 min) would cause soluble oxidized aggregates to reaggregate through an anti-parallel intermolecular ß-sheet, which resulted in lower EAI and ESI, and a higher interfacial tension (22.44 mN/m). The results showed that suitable cavitation jet treatment could adjust the structural and functional features of SOSPI by targeted regulated transformation between the soluble and insoluble components.

[Developing biomass estimation models of young trees in typical plantation on the Qinghai-Tibet Plateau, China.] / é’è—é«˜åŽŸå ¸åž‹äººå·¥æž—å¹¼æ ‘ç”Ÿç‰©é‡æ¨¡åž‹æž„å»º.

Calculation of forest biomass is the basis for global carbon stock estimation, which has been included in national forest inventory projects. The volume-derived biomass method is generally used for trees with diameter at breast height (DBH) larger than 5 cm in most forest carbon sink measurement, which omits young trees (diameter at breast height <6 cm, height >0.3 m) and thus may underestimate ecosystem carbon sink capacity. Based on the biomass data of 137 young trees in five typical plantations on the Tibetan Plateau, independent biomass models were developed using the weighted generalized least squares method, with basic diameter as the predictor instead of DBH. Additive biomass models of controlling directly by proportion functions and controlling by the sum of equations were selected. Additive biomass models for the whole plant and each component were developed by applying weighted nonlinear seemingly uncorrelated regression. The results showed that the binary additive biomass model (R2 reached 0.90-0.99) performed better than the monadic biomass models and independent biomass models for the estimation of total biomass. For different tree species, two forms of the additive models had their own advantages, with neglectable difference in accuracy. From the perspective of forestry production, models of controlling directly by proportion functions were more practical. From the perspective of predictors extraction by remote sensing technology, suitable young tree biomass models were developed for remote sensing estimation. In this study, the additive model had high overall fitting accuracy and could accurately estimate the whole plant and component biomass of young trees in similar climatic environments.

Deciphering the Biological Effects of Radiotherapy in Cancer Cells.

Radiotherapy remains an effective conventional method of treatment for patients with cancer. However, the clinical efficacy of radiotherapy is compromised by the development of radioresistance of the tumor cells during the treatment. Consequently, there is need for a comprehensive understanding of the regulatory mechanisms of tumor cells in response to radiation to improve radiotherapy efficacy. The current study aims to highlight new developments that illustrate various forms of cancer cell death after exposure to radiation. A summary of the cellular pathways and important target proteins that are responsible for tumor radioresistance and metastasis is also provided. Further, the study outlines several mechanistic descriptions of the interaction between ionizing radiation and the host immune system. Therefore, the current review provides a reference for future research studies on the biological effects of new radiotherapy technologies, such as ultra-high-dose-rate (FLASH) radiotherapy, proton therapy, and heavy-ion therapy.

Low compliance to post-screening recommendations in a family-based Helicobacter pylori screening and treatment program: A prospective cohort study.

BACKGROUND: Intra-family transmission is an important Helicobacter pylori (H. pylori) infection route. Family-based screening and treatment of H. pylori is a promising strategy. However, limited data are available on patient compliance with post-screening recommendations for such a strategy. MATERIALS AND METHODS: A prospective cohort study of families from six regions in Shandong, China, from July 2021 to February 2022 was conducted. Demographic characteristics, prior testing, and treatment for H. pylori, prior gastroscopy, symptoms, and family history were collected. Infection status of participants was determined using the 13 C-urea breath test. Infected participants were recommended to undergo eradication treatment, confirmation testing, and gastroscopy per expert consensus. Participants were monitored for 6 months to record recommendation compliance in a real-world setting. Logistic regression models were used to analyze the factors influencing compliance with the recommendations. RESULTS: The study included 1173 individuals from 386 families with the overall infection rate of 36.7%. The recommendation compliance for eradication treatment, confirmation testing, and gastroscopy was 69.3% (271/391), 32.5% (88/271), and 6.1% (19/309), respectively. Factors that increased the risk of lower compliance were male sex (odds ratio [OR], 1.917, 95% confidence interval [CI], 1.233-2.981), and living in a non-urban area (OR, 1.954, 95% CI, 1.241-3.074), for treatment recommendations; having more than one infected family member (OR, 2.138, 95% CI, 1.237-3.698), and a lower family income (¥100,000-¥300,000 per year, OR, 7.247, 95% CI, 1.788-29.363; or <¥100,000 per year, OR, 7.294, 95% CI, 1.832-29.042), for confirmation testing recommendations; and being asymptomatic (OR, 3.009, 95% CI, 1.105-8.196), for gastroscopy recommendations. CONCLUSIONS: Post-screening recommendation compliance for this family-based H. pylori screening and treatment program was unsatisfactory. Further studies focusing on pre-screening education are warranted to improve compliance.

Gastrodin attenuates perfluorooctanoic acid-induced liver injury by regulating gut microbiota composition in mice.

Perfluorooctanoic acid (PFOA) can accumulate in the livers of humans and animals via the food chain, resulting into liver injury, which is closely related to intestinal flora dysbiosis. Gastrodin has been reported to have hepatoprotective effect. However, whether gastrodin can alleviate PFOA-induced liver injury via modulating gut microbiota remains unclear. Herein, a PFOA-induced liver injury model was established by gavage of PFOA (5 mg/kg body weight) in 2% Tween 80 solution once daily for 6 weeks in mice, and then gastrodin in saline (20 mg/kg body weight) was used once daily for 8 weeks to treat liver damage. The biochemical indexes associated with liver function, oxidative stress, and inflammatory factors were examined. Hematoxylin-eosin staining was used to determine the liver histopathological changes. Besides, 16S rRNA sequencing was used to analyze the difference of gut microbiota between the model and treatment groups. The results showed that gastrodin significantly improved the oxidative stress caused by PFOA. Intestinal flora analysis showed that gastrodin treatment significantly increased the relative abundance of probiotics, such as Lactobacillus, Bifidobacterium, and Bacteroides, while the harmful bacteria, including Desulfovibrio were decreased. Gastrodin treatment also significantly increased the level of short-chain fatty acids (SCFAs), such as butyric acid and isobutyric acid. Spearman correlation analysis showed that the composition changes of gut microbiota and SCFAs increase were both beneficial to alleviate the liver injury caused by PFOA. To sum up, gastrodin can effectively alleviate PFOA-induced liver injury through regulating gut microbiota composition.

Transcriptome analysis uncovers the key pathways and candidate genes related to the treatment of Echinococcus granulosus protoscoleces with the repurposed drug pyronaridine.

BACKGROUND: Cystic echinococcosis (CE) is a life-threatening zoonosis caused by the larval form of Echinococcus granulosus tapeworm. Our previous study showed that an approved drug pyronaridine (PND) is highly effective against CE, both in vitro and in an animal model. To identify possible target genes, transcriptome analysis was performed with E. granulosus sensu stricto protoscoleces treated with PND. RESULTS: A total of 1,321 genes were differentially expressed in protoscoleces treated with PND, including 541 upregulated and 780 downregulated genes. Gene ontology and KEGG analyses revealed that the spliceosome, mitogen-activated protein kinase (MAPK) pathway and ATP-binding cassette (ABC) transporters were the top three enriched pathways. Western blot analysis showed that PND treatment resulted in a dose-dependent increase in protein expression levels of EgMKK1 (MKK3/6-like) and EgMKK2 (MEK1/2-like), two members of MAPK cascades. Interestingly, several heat shock protein (HSP) genes were greatly downregulated including stress-inducible HSPs and their constitutive cognates, and some of them belong to Echinococcus-specific expansion of HSP70. CONCLUSIONS: PND has a great impact on the spliceosome, MAPK pathway and ABC transporters, which may underline the mechanisms by which PND kills E. granulosus protoscoleces. In addition, PND downregulates HSPs expression, suggesting a close relationship between the drug and HSPs.

High endemicity of alveolar echinococcosis in Yili Prefecture, Xinjiang Autonomous Region, the People's Republic of China: Infection status in different ethnic communities and in small mammals.

Alveolar echinococcosis (AE) is a life-threatening disease in humans caused by the larval stage of Echinococcus multilocularis. The tapeworm is transmitted between small mammals and dogs/foxes in the Northern Hemisphere. In this study 286 AE cases were reported from eight counties and one city in Yili Prefecture, Xinjiang Autonomous Region, the People's Republic of China from 1989 to 2015 with an annual incidence (AI) of 0.41/100,000. Among the patients, 73.08% were diagnosed in the last 11 years. Four counties in the high mountainous areas showed higher AI (0.51-1.22 cases/100,000 residents) than the four counties in low level areas (0.19-0.29/100,000 residents). The AI of AE in Mongolian (2.06/100,000 residents) and Kazak (0.93/100,000 residents) ethnic groups was higher than the incidence in other ethnic groups indicating sheep-farming is a risk for infection given this activity is mainly practiced by these two groups in the prefecture. A total of 1411 small mammals were captured with 9.14% infected with E. multilocularis metacestodes. Microtus obscurus was the dominant species in the mountain pasture areas with 15.01% of the voles infected, whereas Mus musculus and Apodemus sylvaticus were the dominant small mammals in the low altitude areas. Only 0.40% of A. sylvaticus were infected with E. multilocularis. PCR amplification and sequencing analysis of the mitochondrial cox1 gene showed that E. multilocularis DNA sequences from the small mammals were identical to isolates of local human AE cases. The overall results show that Yili Prefecture is a highly endemic area for AE and that the high-altitude pasture areas favorable for M. obscurus may play an important role in its transmission in this region.

Prevalence and Molecular Characterization of Echinococcus granulosus Sensu Stricto in Northern Xinjiang, China.

Echinococcus granulosus is an important zoonotic parasite globally causing cystic echinococcosis (CE) in humans and animals. In this study, prevalence of CE and variation of cox1 gene sequence were analyzed with isolates E. granulosus collected from different areas in northern Xinjiang, China. The survey showed that 3.5% of sheep and 4.1% of cattle were infected with CE. Fragment of cox1 was amplified from all the positive sheep and cattle samples by PCR. In addition, 26 positive samples across the 4 areas were included. The isolates were all E. granulosus sensu stricto (s.s.) containing 15 haplotypes (Hap1-15), and clustered into 2 genotypes, G1 (90.1%, 91/101) and G3 (9.9%, 10/101). Hap1 was the most common haplotype (48.5%, 49/101). Hap9 were found in humans samples, indicating that sheep and cattle reservoir human CE. It is indicate that E. granulosus may impact on control of CE in livestock and humans in the region.

Echinococcus granulosus Infection Results in an Increase in Eisenbergiella and Parabacteroides Genera in the Gut of Mice.

Cystic echinococcosis (CE) is a chronic infectious disease caused by Echinococcus granulosus. To confirm whether the infection impacts on the gut microbiota, we established a mouse model of E. granulosus infection in this study whereby BALB/c mice were infected with micro-cysts of E. granulosus. After 4 months of infection, fecal samples were collected for high-throughput sequencing of the hypervariable regions of the 16S rRNA gene. Sequence analysis revealed a total of 13,353 operational taxonomic units (OTUs) with only 40.6% of the OTUs having genera reference information and 101 of the OTUs were significantly increased in infected mice. Bioinformatics analysis showed that the common core microbiota were not significantly changed at family level. However, two genera (Eisenbergiella and Parabacteroides) were enriched in the infected mice (P AMOV A < 0.05) at genus level. Functional analysis indicated that seven pathways were altered in the E. granulosus Infection Group compared with the Uninfected Group. Spearman correlation analysis showed strong correlations of IgG, IgG1 and IgG2a with nine major genera. E. granulosus cyst infection may change the gut microbiota which may be associated with metabolic pathways.

Dog vaccination with EgM proteins against Echinococcus granulosus.

BACKGROUND: Dogs play a pivotal role in the transmission of cystic echinococcosis (CE), a zoonosis caused by the tapeworm Echinococcus granulosus. We showed previously that dogs vaccinated with two E. granulosus adult-worm specific proteins, EgM9 and EgM123, emulsified with Freund's adjuvants induced significant protective efficacy in terms of reduction in worm burden and egg production after 45 days post-infection. It was not known whether this protection can be sustained using adjuvants suitable for use in dogs. METHODS: Recombinant EgM9 and EgM123 were mixed with Quil A or ISCOMs for vaccinating dogs. After three vaccine injections, all the dogs were orally challenge-infected with 200 000 protoscoleces of E. granulosus. After 45 days of infection, all the dogs were euthanized and necropsied for collecting and counting E. granulosus worms. Immunoglobins, including the IgG subclasses IgG1 and IgG2, were detected in the sera of vaccinated dogs by ELISA. To determine whether the protection efficacy could be maintained after 45 days post-infection, we implemented a longevity trial to count eggs in dog faeces for 170 days after infection. RESULTS: The dogs vaccinated with EgM9 and EgM123 mixed with Quil A and ISCOMs showed similar protective efficacy as the proteins emulsified with Freund's adjuvants in our previous study in terms of reduction of worms and eggs at 45 days post-infection. The longevity trial showed that EgM9 protein-vaccinated group released lower number of eggs per gram compared with the egg counts in the control dogs during the dog trial study. CONCLUSION: EgM9 and EgM123 are thus suitable vaccine candidates against E. granulosus infection in dogs.

In vitro and in vivo efficacies of novel carbazole aminoalcohols in the treatment of cystic echinococcosis.

OBJECTIVES: Cystic echinococcosis (CE), caused by the cestode Echinococcus granulosus, is a worldwide chronic zoonosis. Current chemotherapeutic options are limited to albendazole and mebendazole, which only exert parasitostatic effects and have to be administered at high dosages for long periods. In an effort to find alternative treatment options, the in vitro and in vivo efficacies of novel carbazole aminoalcohols were evaluated. METHODS: Carbazole aminoalcohols were tested against E. granulosus protoscoleces in vitro and metacestodes ex vivo. The in vivo chemotherapeutic effect of representative compounds was assessed in experimentally infected mice. Oral and intravenous pharmacokinetic profiles were determined in mice. RESULTS: The carbazole aminoalcohols exhibited potent protoscolicidal activity with LC50 values ranging from 18.2 to 34.3 µM. Among them, compounds 2 and 24 killed all ex vivo cultured metacestodes at concentrations of 34.3 and 30.6 µM. In vivo studies showed that oral administration of compounds 2 and 24 (25 mg/kg/day) for 30 days led to reductions of 68.4% and 54.3% in parasite weight compared with the untreated group (both groups: P < 0.001). Compound 2 (25 mg/kg/day) and compound 24 (50 mg/kg/day) induced significantly higher cyst mortality rates in comparison with that of the albendazole group (both groups: P < 0.01). Analysis of cysts collected from compound 2- or 24-treated mice by transmission electron microscopy revealed a drug-induced structural destruction. The structural integrity of the germinal layer was lost, and the majority of the microtriches disappeared. Pharmacokinetic profiling of compounds 2 and 24 revealed low clearance and decent oral bioavailability (>70%). CONCLUSIONS: Our study identifies carbazole aminoalcohols as a class of novel anti-CE agents. Compounds 2 and 24 represent promising drug candidates in anti-CE chemotherapy.

xCT deficiency induces autophagy via endoplasmic reticulum stress activated p38-mitogen-activated protein kinase and mTOR in sut melanocytes.

xCT, the functional subunit of the system xc(-) encoded by the Slc7a11 gene, plays an important role in maintaining intracellular glutathione (GSH) levels. In previous study, we have indicated that xCT deficiency induces OS and that OS triggers apoptosis through JNK pathway, however, this induction of apoptotic features did not fully explain the cell death induced by xCT deficiency. In the current study, we demonstrated that sut melanocytes of xCT deficiency showed activation of both ER stress and autophagy. And that the activation of autophagy by xCT deficiency was mediated by ER stress induced activation of p38 MAPK and NF-κB pathways and subsequently inhibited functions of Akt/mTOR/p70S6K survival pathways, ultimately led to autophagic cell death of sut melanocytes. Our novel results provided important insights into understanding the mechanism associated with xCT deficiency.