bluuebunny/crossref_metadata_2025_split huggingface dataset:
Integrating peripheral blood and brain transcriptomics to identify immunological features associated with Alzheimer’s disease in mild cognitive impairment patients
Authors: Qian Xiao-hang , Liu Xiao-li , Chen Sheng-di , Tang Hui-dong 
Published: September 2022

BackgroundImmune system dysfunction has been proven to be an important pathological event in Alzheimer’s disease (AD). Mild cognitive impairment (MCI), as a transitional stage between normal cognitive function and AD, was an important research object for the screening of early diagnostic markers and therapeutic targets for AD. However, systematic assessment of peripheral immune system changes in MCI patients and consistent analysis with that in the CNS were still lacking.MethodsPeripheral blood transcriptome data from the AddNeuroMed Cohort (n = 711) was used as a training dataset to assess the abundance of 24 immune cells through ImmuCellAI and to identify MCI-related immune signaling pathways and hub genes. The expression level of the immune hub gene was validated in peripheral blood (n = 587) and brain tissue (78 entorhinal cortex, 140 hippocampi, 91 temporal cortex, and 232 frontal cortex) validation datasets. Finally, reliable immune hub genes were applied for Gene Set Enrichment Analysis and correlation analysis of AD pathological characteristics.ResultsMCI patients have early changes in the abundance of various types of immune cells in peripheral blood, accompanied by significant changes in NF-kB, TNF, JAK-STAT, and MAPK signaling pathways. Five hub immune-related differentially expressed genes (NFKBIA, CD4, RELA, CASP3, and HSP90AA1) were screened by the cytoHubba plugin in Cytoscape and the least absolute shrinkage and selection operator (LASSO) regression. Their expression levels were significantly correlated with infiltration score and the abundance of monocytes, natural killer cells, Th2 T cells, T follicular helper cells, and cytotoxic T cells. After validation with independent datasets derived from peripheral blood and brain, RELA and HSP90AA1 were identified as two reliable immune hub genes in MCI patients and had consistent changes in AD. The Gene Set Enrichment Analysis (GSEA) showed that their expression levels were closely associated with Alzheimer’s disease, JAK-STAT, calcium signaling pathway, etc. In addition, the expression level of RELA was positively correlated with β- and γ-secretase activity and Braak stage. The expression level of HSP90AA1 was negatively correlated with α- and β-secretase activity.ConclusionImmune system dysfunction was an early event in AD. It provides a new target for the early diagnosis and treatment of AD.
Andrographolide promote the growth and immunity of Litopenaeus vannamei, and protects shrimps against Vibrio alginolyticus by regulating inflammation and apoptosis via a ROS-JNK dependent pathway
Authors: Yin Xiaoli , Zhuang Xueqi , Luo Weitao , Liao Meiqiu , Huang Lin , Cui Qiqian , Huang Jiayi , Yan Chunxia , Jiang Zixiang , Liu Yuan , Wang Weina 
Published: September 2022

Vibrio alginolyticus (V. alginolyticus) is one of the major pathogens causing mass mortality of shrimps worldwide, affecting energy metabolism, immune response and development of shrimps. In the context of the prohibition of antibiotics, it is necessary to develop a drug that can protect shrimp from V. alginolyticus. Andrographolide (hereinafter called Andr), a traditional drug used in Chinese medicine, which possesses diverse biological effects including anti-bacteria, antioxidant, immune regulation. In this study, we investigated the effect of Andr on growth, immunity, and resistance to V. alginolyticus infection of Litopenaeus vannamei (L. vannamei) and elucidate the underlying molecular mechanisms. Four diets were formulated by adding Andr at the dosage of 0 g/kg (Control), 0.5 g/kg, 1 g/kg, and 2 g/kg in the basal diet, respectively. Each diet was randomly fed to one group with three replicates of shrimps in a 4-week feeding trial. The results showed that dietary Andr improved the growth performance and non-specific immune function of shrimps. L. vannamei fed with Andr diets showed lower mortality after being challenged by V. alginolyticus. After 6 h of V. alginolyticus infection, reactive oxygen species (ROS) production, tissue injury, apoptosis, expression of inflammatory factors (IL-1 β and TNFα) and apoptosis-related genes (Bax, caspase3 and p53) were increased in hemocytes and hepatopancreas, while feeding diet with 0.5 g/kg Andr could inhibit the increase. Considering that JNK are important mediators of apoptosis, we examined the influence of Andr on JNK activity during V. alginolyticus infection. We found that Andr inhibited JNK activation induced by V. alginolyticus infection on L. vannamei. The ROS scavenger N-acetyl-l-cysteine (NAC) suppressed V. alginolyticus-induced inflammation and apoptosis, suggesting that ROS play an important role in V. alginolyticus-induced inflammation and apoptosis. Treated cells with JNK specific activator anisomycin, the inflammation and apoptosis inhibited by Andr were counteracted. Collectively, Andr promote the growth and immunity of L. vannamei, and protects shrimps against V. alginolyticus by regulating inflammation and apoptosis via a ROS-JNK dependent pathway. These results improve the understanding of the pathogenesis of V. alginolyticus infection and provide clues to the development of effective drugs against V. alginolyticus.
Proposal for standardizing normal insulin ranges in Brazilian patients and a new classification of metabolic syndrome
Authors: Chocair Pedro Renato , de Menezes Neves Precil Diego Miranda , Sato Victor Augusto Hamamoto , Mohrbacher Sara , Oliveira Érico Souza , Pereira Leonardo Victor Barbosa , Bales Alessandra Martins , da Silva Fagner Pereira , Duley John A. , Cuvello-Neto Américo Lourenço 
Published: September 2022

BackgroundInsulin resistance and/or hyperinsulinemia are closely linked to adiposity, metabolic syndrome (MetS) and prolonged inflammatory processes.MethodsWe retrospectively analyzed 1,018 adult individuals with a mean age of 46 years (74% male) and classified them as: Metabolically normal: without any of the five criteria of the International Diabetes Federation (IDF) used for the diagnosis of MetS, plus normal fasting insulin (Men &lt; 8 mU/L, Women &lt; 10 mU/L); Level 1 MetS: with one or two IDF criteria, plus hyperinsulinemia (Men: ≥ 8 mU/L), and Women: ≥ 10 mU/L); Level 2 MetS: with three or more IDF criteria, plus hyperinsulinemia.ResultsThe mean values for fasting insulinemia in metabolically normal individuals was 4.6 ± 1.8 mU/L and 5.6 ± 2.3 mU/L, while their means for the Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) were 1.0 and 1.2 for men and women, respectively. In addition, the mean values for insulin (and HOMA-IR) for individuals with two normal anthropometric parameters (body mass index and waist girth), or two normal anthropometric parameters plus no IDF criteria, were similar to the metabolically normal group. Based on the obtained mean + 2 SD, we established the following insulin (and HOMA-IR) values as diagnostic cut-offs for hyperinsulinemia: Men: ≥ 8 mU/L (≥ 1.5), and Women: ≥ 10 mU/L (≥ 2.0). The mean serum insulin was significantly higher for individuals with Level 1 MetS (approx. 9 mU/L for both genders) compared with metabolically normal individuals, as was the prevalence of hepatic steatosis, which was more evident in men. Thus, the presence of one or two abnormal IDF criteria, combined with hyperinsulinemia and/or raised HOMA-IR, suggests the presence of MetS and insulin resistance. Patients of both genders with Level 2 MetS had higher serum insulin and/or HOMA-IR values than Level 1, as well as a higher prevalence of hypertension and hepatic steatosis, being more pronounced among men. The process was progressive and proportional to the degree of hyperinsulinemia.ConclusionIt is proposed that intervention against MetS progression should be started in individuals with Level 1 MetS, rather than waiting for more criteria for diagnostic confirmation, which this should help to reduce the occurrence of known complications such as type 2 diabetes, atherosclerosis, hypertension, and chronic kidney disease, among others.
Serum creatinine to cystatin C ratio and cognitive function among middle-aged and older adults in China
Authors: Zhu Yueli , Tan Zhongju , Li Shumin , Zhu Feng , Qin Chengfan , Zhang Qin , Yang Yunmei 
Published: September 2022

BackgroundThe sarcopenia index (SI, serum creatinine/serum cystatin C × 100) is recently suggested to be a reliable marker for sarcopenia. It has been reported that sarcopenia is associated with poorer cognition. The purpose of this study was to evaluate the correlation between SI and cognitive function among middle-aged and older adults from the China Health and Retirement Longitudinal Study (CHARLS).Materials and methodsA total of 6,442 participants ≥45 years of age were enrolled in this study from CHARLS between 2011 and 2012. Cognitive function was assessed by interview-based measurements, including orientation and attention, episodic memory, visuo-construction, and the total cognitive function. SI was calculated by serum creatinine (mg/dL)/cystatin C (mg/L) × 100. One-way analysis of variance (ANOVA) was used to compare the differences among groups divided according to SI quartiles by gender. Both linear and logistic regression models were applied to investigate the relationship between SI and cognitive function.ResultsAfter adjustment for potential confounders, we found SI was significantly and positively correlated with total cognitive function scores both in males and females [β = 0.014, 95% confidence interval (CI) 0.007 to 0.021, P &lt; 0.001; β = 0.011, 95 CI% 0.003 to 0.018, P = 0.004; respectively]. Similarly, when the total cognitive function score was treated as a categorical variable according to quartiles in males and females, higher SI was related to better total cognitive function scores in both males and females [odds ratio (OR) = 1.147, 95% CI 1.028 to 1.279, P = 0.014; OR = 1.219, 95% CI 1.106 to 1.344, P &lt; 0.001; respectively] following adjustment for confounders.ConclusionsLower sarcopenia index was correlated with a higher prevalence of cognitive impairment among middle-aged and older adults in China.
A predictive hemodynamic model based on risk factors for ruptured mirror aneurysms
Authors: Hu Sheng-qi , Chen Ru-dong , Xu Wei-dong , Li Hua , Yu Jia-sheng 
Published: September 2022

ObjectivesTo identify hemodynamic risk factors for intracranial aneurysm rupture and establish a predictive model to aid evaluation.MethodsWe analyzed the hemodynamic parameters of 91 pairs of ruptured mirror aneurysms. A conditional univariate analysis was used for the continuous variables. A conditional multivariate logistic regression analysis was performed to identify the independent risk factors. Differences where p &lt; 0.05 were statistically significant. A predictive model was established based on independent risk factors. Odds ratios (ORs) were used to score points. The validation cohort consisted of 189 aneurysms. Receiver operating characteristic curves were generated to determine the cutoff values and area under the curves (AUCs) of the predictive model and independent risk factors.ResultsThe conditional multivariate logistic analysis showed that the low shear area (LSA) (OR = 70.322, p = 0.044, CI = 1.112–4,445.256), mean combined hemodynamic parameter (CHP) (&gt;0.087) (OR = 3.171, p = 0.034, CI = 1.089–9.236), and wall shear stress gradient (WSSG) ratio (&gt;893.180) (OR = 5.740, p = 0.003, CI = 1.950–16.898) were independent risk factors. A prediction model was established: 23*LSA + 1*CHP mean (&gt;0.087: yes = 1, no = 0) + 2 * WSSG ratio (&gt;893.180: yes = 1, no = 0). The AUC values of the predictive model, LSA, mean CHP (&gt;0.087), and WSSG ratio (&gt;893.180) were 0.748, 0.700, 0.654, and 0.703, respectively. The predictive model and LSA cutoff values were 1.283 and 0.016, respectively. In the validation cohort, the predictive model, LSA, CHP (&gt;0.087), and WSSG ratio (&gt;893.180) were 0.736, 0.702, 0.689, and 0.706, respectively.ConclusionsLSA, CHP (&gt;0.087), and WSSG ratio (&gt;893.180) were independent risk factors for aneurysm rupture. Our predictive model could aid practical evaluation.
Newborns' clinical conditions are correlated with the neonatal assessment manual scorE (NAME)
Authors: Manzotti Andrea , Cerritelli Francesco , Lombardi Erica , La Rocca Simona , Biasi Pamela , Chiera Marco , Galli Matteo , Lista Gianluca 
Published: September 2022

ObjectiveTo investigate the relationship between the Neonatal Assessment Manual scorE (NAME) and newborns' clinical condition on a large number of infants. The NAME model was developed as an instrument to assess the infant's general conditions, especially in NICUs, by evaluating how the infant's body responds to an external stressor such as static touch. Previous studies, employing experienced assessors, showed good validity indices as well as high inter-rater reliability.Study designNewborns were recruited at the “Vittore Buzzi” Pediatric Hospital NICU ward in Milan and their clinical conditions were collected through a standardized form—the complexity index. Two manual practitioners assessed all eligible newborns using the NAME scores. Data was analyzed using Kendall's τ correlation and odds ratio (OR) to assess the relationship between the NAME scores and the complexity index.ResultsTwo hundred two newborns (46% female; 34.1 w ± 4.3; birth weight of 2,093.4 gr ± 879.8) entered the study. The Kendall's correlation between the clinical conditions (complexity index) and the NAME score was −0.206 [95% CI: (−0.292, −0.116), p-value &lt; 0.001], corresponding to an OR of 0.838 [95% CI: (0.757, 0.924), p-value &lt; 0.001]. Further exploratory analyses showed significant correlation between gestational age, birth weight and NAME scores.ConclusionThe present paper adds evidence to the NAME model validity by demonstrating its applicability in the clinical neonatological context.
Development of a novel Bruton’s tyrosine kinase inhibitor that exerts anti-cancer activities potentiates response of chemotherapeutic agents in multiple myeloma stem cell-like cells
Authors: Elbezanti Weam Othman , Al-Odat Omar S. , Chitren Robert , Singh Jaikee Kumar , Srivastava Sandeep Kumar , Gowda Krishne , Amin Shantu , Robertson Gavin P. , Nemmara Venkatesh V. , Jonnalagadda Subash C. , Budak-Alpdogan Tulin , Pandey Manoj K. 
Published: September 2022

Despite recent improvements in multiple myeloma (MM) treatment, MM remains an incurable disease and most patients experience a relapse. The major reason for myeloma recurrence is the persistent stem cell-like population. It has been demonstrated that overexpression of Bruton’s tyrosine kinase (BTK) in MM stem cell-like cells is correlated with drug resistance and poor prognosis. We have developed a novel small BTK inhibitor, KS151, which is unique compared to other BTK inhibitors. Unlike ibrutinib, and the other BTK inhibitors such as acalabrutinib, orelabrutinib, and zanubrutinib that covalently bind to the C481 residue in the BTK kinase domain, KS151 can inhibit BTK activities without binding to C481. This feature of KS151 is important because C481 becomes mutated in many patients and causes drug resistance. We demonstrated that KS151 inhibits in vitro BTK kinase activities and is more potent than ibrutinib. Furthermore, by performing a semi-quantitative, sandwich-based array for 71-tyrosine kinase phosphorylation, we found that KS151 specifically inhibits BTK. Our western blotting data showed that KS151 inhibits BTK signaling pathways and is effective against bortezomib-resistant cells as well as MM stem cell-like cells. Moreover, KS151 potentiates the apoptotic response of bortezomib, lenalidomide, and panobinostat in both MM and stem cell-like cells. Interestingly, KS151 inhibits stemness markers and is efficient in inhibiting Nanog and Gli1 stemness markers even when MM cells were co-cultured with bone marrow stromal cells (BMSCs). Overall, our results show that we have developed a novel BTK inhibitor effective against the stem cell-like population, and potentiates the response of chemotherapeutic agents.
UGT2B7 gene polymorphism and linkage disequilibrium in pediatric epileptic patients and their influence on sodium valproate monotherapy: A cohort study
Authors: Adiga Sachidananda , PB Nandit , Adiga Usha , Shenoy Vijaya 
Published: September 2022

Background: Uridine 5′-diphospho glucuronosyl transferase (UGT) is the main enzyme responsible for the glucuronide conjugation, the principal metabolic pathway of sodium valproate. The objective of the study was to explore if there was an association between the UGT2B7 genetic polymorphism and clinical efficacy and safety in paediatric epileptic patients on sodium valproate monotherapy.Methods and materials: The cohort study included 100 pediatric epileptic patients aged 2–18 years who had been on sodium valproate monotherapy for at least 1 month. PCR-RFLP was carried out to assess the genetic polymorphism patterns of UGT2B7 (C161T, A268G, G211T). Based on the extent of seizure control throughout the 1-year follow-up, clinical outcome was assessed in terms of responders and non-responders. Hepatic, renal, and other lab parameters were assayed to determine safety. The SNPstat web software was used to calculate linkage disequilibrium.Results: Out of 100 patients, CC (38%), CT (43%), TT (19%) pattern was observed in UGT2B7 (C161T) gene, AA (15%), AG (39%), GG (46%) in (A268G) gene and GG (80%), GT (18%), TT (02%) in (G211T) gene. There was no statistical difference in clinical outcome with distinct UGT2B7 genetic polymorphism patterns, according to the findings. With low D′ and R2 values, linkage disequilibrium between alleles was statistically insignificant. However, the associations of C161T and G211T with treatment response were significant (p = 0.014) in determining treatment response.Conclusion: Our findings show that the genetic variation of UGT2B7 had no bearing on the clinical outcome of epilepsy. Gene interactions, on the other hand, had an impact on treatment response.
Mailuoshutong pill for varicocele-associated male infertility—Phytochemical characterisation and multitarget mechanism
Authors: Lv Dongfang , Ji Yun , Zhang Qian , Shi Zhuozhuo , Chen Tengfei , Zhang Chao , Wang Xiangyun , Ren Taotao , Gao Zhaowang , Zhong Chongfu 
Published: September 2022

Background: Varicocele (VC) is a relatively common and treatable cause of male infertility. Mailuoshutong pill (MLST), a traditional Chinese patent medicine, is widely used for treating varicose vein disease, but the underlying mechanism of MLST on varicocele-associated male infertility is unclear.Objective: To reveal the phytochemical characterisation and multitarget mechanism of MLST on varicocele-associated male infertility.Methods: The components in MLST were determined using UHPLC-MS/MS. Through network analysis, we constructed the “Drug-Components-Targets-Disease” network and predicted the potential biological functions and signaling pathways of MLST. Finally, the therapeutic effects and potential mechanisms of MLST were discovered by pharmacological experiments.Results: By network analysis, the “Drug-Components-Targets-Disease” network was constructed, 62 components such as apigenin, limonin, kaempferol, and obacunoic acid may be the main active components of MLST for varicocele-associated male infertility, 28 targets such as VEGFA, PIK3CA, AKT1, and MTOR are considered as hub targets, signaling pathways such as HIF-1, Estrogen, PI3K/Akt, and mTOR may be key pathways for MLST against varicocele-associated male infertility. Through pharmacological experiments, we found that MLST ameliorated VC-induced testicular atrophy. Further histomorphology showed that MLST reduced VC-induced damage to testicular spermatogonia and seminiferous tubule, while MLST reduced ROS and MDA levels and increased antioxidant enzymes (GSH, GSH-Px, SOD, and CAT) levels. TUNEL staining and immunofluorescence showed that MLST reduced VC-induced apoptosis in testicular tissue, decreased BAX, and increased BCL2. Western blot results showed that MLST decreased the phosphorylation of PI3K, AKT, and mTOR proteins, and decreased the expression of HIF1α.Conclusion: The phytochemical characterisation and multitarget mechanism of MLST on varicocele-associated male infertility were discovered using network analysis and pharmacological experiments. We verified that MLST can inhibit the activation of the PI3K/Akt/mTOR signaling pathway, reduce the expression of HIF1α, and further attenuate VC-induced oxidative stress and apoptosis in the testis. These findings provide evidence for the therapeutic role of MLST in varicocele-associated male infertility.
The microbiota changes of the brown dog tick, Rhipicephalus sanguineus under starvation stress
Authors: An Liping , Bhowmick Biswajit , Liang Dejuan , Suo Penghui , Liao Chenghong , Zhao Jianguo , Han Qian 
Published: September 2022

Rhipicephalus sanguineus, the brown dog tick, is the most widespread tick in the world and a predominant vector of multiple pathogens affecting wild and domestic animals. There is an increasing interest in understanding the role of tick microbiome in pathogen acquisition and transmission as well as in environment–vector interfaces. Several studies suggested that the tick microbial communities are under the influence of several factors including the tick species, dietary bloodmeal, and physiological stress. Compared with insects, very little of the microbial community is known to contribute to the nutrition of the host. Therefore, it is of significance to elucidate the regulation of the microbial community of Rh. Sanguineus under starvation stress. Starvation stress was induced in wild-type adults (1 month, 2 months, 4 months, 6 months) and the microbial composition and diversity were analyzed before and after blood feeding. After the evaluation, it was found that the microbial community composition of Rh. sanguineus changed significantly with starvation stress. The dominant symbiotic bacteria Coxiella spp. of Rh. sanguineus gradually decreased with the prolongation of starvation stress. We also demonstrated that the starvation tolerance of Rh. sanguineus was as long as 6 months. Next, Coxiella-like endosymbionts were quantitatively analyzed by fluorescence quantitative PCR. We found a pronounced tissue tropism in the Malpighian tubule and female gonad, and less in the midgut and salivary gland organs. Finally, the blood-fed nymphs were injected with ofloxacin within 24 h. The nymphs were allowed to develop into adults. It was found that the adult blood-sucking rate, adult weight after blood meal, fecundity (egg hatching rate), and feeding period of the newly hatched larvae were all affected to varying degrees, indicating that the removal of most symbiotic bacteria had an irreversible effect on it.