bluuebunny/crossref_metadata_2025 huggingface dataset:
The Application of Principal Component Analysis on Clinical and Biochemical Parameters Exemplified in Children With Congenital Adrenal Hyperplasia
Authors: Ljubicic Marie Lindhardt , Madsen Andre , Juul Anders , Almstrup Kristian , Johannsen Trine Holm
Published: September 2021

Purpose

Principal component analysis (PCA) is a mathematical model which simplifies data into new, combined variables. Optimal treatment of pediatric congenital adrenal hyperplasia (CAH) remains a challenge and requires evaluation of all biochemical and clinical markers. The aim of this study was to introduce PCA methodology as a tool to optimize management in a cohort of pediatric and adolescent patients with CAH by including adrenal steroid measurements and clinical parameters.

Methods

This retrospective, longitudinal cohort of 33 children and adolescents with CAH due to 21-hydroxylase deficiency included 406 follow-up observations. PCAs were applied to serum hormone concentrations and compared to treatment efficacy evaluated by clinical parameters.

Results

We provide and describe the first PCA models with hormone parameters denoted in sex- and age-adjusted standard deviation (SD) scores to comprehensibly describe the combined ‘endocrine profiles’ of patients with classical and non-classical CAH, respectively. Endocrine profile scores were predictive markers of treatment efficacy for classical (AUC=92%; accuracy 95%; p=1.8e-06) and non-classical CAH (AUC=80%; accuracy 91%; p=0.004). A combined PCA demonstrated clustering of patients with classical and non-classical CAH by serum 17-hydroxyprogesterone (17-OHP) and dehydroepiandrosterone-sulphate (DHEAS) concentrations.

Conclusion

As an example of the possibilities of PCA, endocrine profiles were successfully able to distinguish between patients with CAH according to treatment efficacy and to elucidate biochemical differences between classical and non-classical CAH.
Progestin-Primed Ovarian Stimulation Protocol for Patients in Assisted Reproductive Technology: A Meta-Analysis of Randomized Controlled Trials
Authors: Guan Shaogen , Feng Yuezhi , Huang Yonghan , Huang Jia
Published: September 2021

Objectives

Progestin-primed ovarian stimulation (PPOS) is a new ovarian stimulation protocol that can block the luteinizing hormone (LH) surge through progesterone instead of traditional down regulating or gonadotropin-releasing hormone (GnRH) antagonist, and in order to achieve multi-follicle recruitment. This paper aims to investigate the effectiveness of PPOS and its suitability for infertile patients with different ovarian reserve functions.

Methods

We searched published randomized controlled trials (RCTs) about PPOS on Cochrane Library, PubMed, Embase, and Web of Science. The search period spanned from January 1, 2015 to November 16, 2020. The data were extracted, and the meta-analysis was performed on ovarian stimulation as well as embryological and clinical outcomes. The outcomes were pooled by a random effects model, and the risk of heterogeneity was evaluated. Subgroup analysis was performed for different ovarian reserve patients.

Results

The clinical pregnancy rates and live birth or ongoing pregnancy rates with the PPOS protocol were not different from those with the control group. In the diminished ovarian reserve (DOR) subgroup, the PPOS protocol had a lower rate of premature LH surge [RR = 0.03, 95% CI = 0.01 to 0.13, p < 0.001]. The PPOS protocol had a lower rate of ovarian hyperstimulation syndrome (OHSS) [RR = 0.52, 95% CI = 0.36 to 0.76, p < 0.001, I2 = 0.00%]. The secondary outcomes showed that the number of oocytes retrieved, MII oocytes, and viable embryos was higher than that of the control protocol in DOR patients [(MD = 0.33, 95% CI = 0.30 to 0.36, p < 0.001), (MD = 0.30, 95% CI = 0.27 to 0.33, p < 0.001), (MD = 0.21, 95% CI = 0.18 to 0.24, p < 0.001)] and normal ovarian reserve (NOR) patients [(MD = 1.41, 95% CI = 0.03 to 2.78, p < 0.001), (MD = 1.19, 95% CI = 0.04 to 2.35, p < 0.001), (MD = 1.01, 95% CI = 0.21 to 1.81, p = 0.01)].

Conclusion

The findings suggest that PPOS is an effective ovarian stimulation protocol and is beneficial for patients with different ovarian reserve functions, which needs to be validated in more RCTs with larger samples.
Secular Trends in the Epidemiologic Patterns of Thyroid Cancer in China Over Three Decades: An Updated Systematic Analysis of Global Burden of Disease Study 2019 Data
Authors: Li Yongze , Piao Jianming , Li Min
Published: September 2021

Background

Thyroid cancer is the most common malignant endocrine disease worldwide. The changing epidemiologic pattern of thyroid cancer at the national level in China has remained unknown over the last three decades.

Methods

Following the general analytical strategy used in the Global Burden of Disease Study (GBD) 2019, the age- and sex-specific incidence, mortality, and prevalence rates of thyroid cancer in China were analyzed. Trends in the incidence, mortality, prevalence, and disability-adjusted life years (DALYs) due to thyroid cancer from 1990 to 2019 were assessed by joinpoint regression analysis. Age, period, and cohort effects on incidence were estimated by an age-period-cohort model.

Results

From 1990 to 2019, the age-standardized prevalence and incidence rates significantly increased in both males and females, and the age-standardized mortality rate decreased in females but increased in males. Moreover, the increments in all the age-standardized measures of thyroid cancer in China were higher in males than in females. The age effect showed that those aged 40–44 years had the highest relative risk (RR) among females, and the RR increased with age among males. The incidence increased with time and began to substantially increase in 2009. The cohort effect showed that the incidence decreased in successive birth cohorts.

Conclusions

The burden of thyroid cancer in China showed unexpected patterns that varied by sex, age, and year. Notably, males had higher average annual percentage changes in thyroid cancer incidence and mortality rates than females. More attention should be given to improving the thyroid cancer burden in males in China.
Case Report: Low Bone and Normal Lean Mass in Adolescents With Complete Androgen Insensitivity Syndrome
Authors: Misakian Aaron , McLoughlin Michelle , Pyle Louisa C. , Kolon Thomas F. , Kelly Andrea , Vogiatzi Maria G.
Published: September 2021

Introduction

Osteopenia and osteoporosis have been reported in adults with Complete Androgen Insensitivity Syndrome (CAIS). Little is known about changes in bone mineral density (BMD) in adolescents with CAIS and whether it is affected by early gonadectomy. Body composition data have not been reported.

Methods

Single-center, retrospective study of CAIS adolescents who underwent dual-energy x-ray absorptiometry (DXA) (Hologic, Horizon A). Body composition is presented as lean and fat mass indices (LMI, FMI). Z-scores for lumbar spine areal BMD (LBMD), total body less head (TBLH), bone mineral content (BMC), LMI, and FMI were calculated using female normative data. Results are expressed as median and min, max.

Results

Six females with genetically confirmed CAIS were identified—one with intact gonads and five with history of gonadectomy at 2–11 months. In the subject with intact gonads, LBMD-Z and TBLH BMC-Z were −1.56 and −1.26, respectively, at age 16 years. Among those with gonadectomy, LBMD-Z was −1.8 (−3.59 to 0.49) at age 15.6 years (12–16.8) and decreased in all three subjects who had longitudinal follow-up despite hormone replacement therapy (HRT). Adherence to HRT was intermittent. LMI-Z and FMI-Z were 0.1 (−1.39 to 0.7) and 1.0 (0.22 to 1.49), respectively.

Conclusions

These limited data indicate that adolescents with CAIS have bone mass deficit. Further studies are needed to understand the extent of BMD abnormalities and the effect of gonadectomy, especially early in childhood, and to establish the optimal HRT regimen for bone accrual. Data on lean mass are reassuring.
A Novel Scoring System for Predicting the Metastases of Posterior Right Recurrent Laryngeal Nerve Lymph Node Involvement in Patients With Papillary Thyroid Carcinoma by Preoperative Ultrasound
Authors: Lu Kai-Ning , Zhang Yu , Da Jia-Yang , Zhou Tian-han , Zhao Ling-Qian , Peng You , Pan Gang , Shi Jing-Jing , Zhou Li , Ni Ye-Qin , Luo Ding-Cun
Published: September 2021

Objective

Our goal was to investigate the correlation between papillary thyroid carcinoma (PTC) characteristics on ultrasonography and metastases of lymph nodes posterior to the right recurrent laryngeal nerve (LN-prRLN). There is still no good method for clinicians to judge whether a patient needs LN-prRLN resection before surgery, and we also wanted to establish a new scoring system to determine whether patients with papillary thyroid carcinoma require LN-prRLN resection before surgery.

Patients and Methods

There were 482 patients with right or bilateral PTC who underwent thyroid gland resection from December 2015 to December 2017 recruited as study subjects. The relationship between the PTC characteristics on ultrasonography and the metastases of LN-prRLN was analyzed by univariate and logistic regression analyses. Based on the risk factors identified in univariate and logistic regression analysis, a nomogram-based LN-prRLN prediction model was established.

Result

LN-prRLN were removed from all patients, of which 79 had LN-prRLN metastasis, with a metastasis rate of 16.39%. Multivariate logistic regression analysis revealed that LN-prRLN metastasis was closely related to sex, age, blood supply, larger tumors (> 1 cm) and capsular invasion. A risk prediction model has been established and fully verified. The calibration curve used to evaluate the nomogram shows that the consistency index was 0.75 ± 0.065.

Conclusion

Preoperative clinical data, such as sex, age, abundant blood supply, larger tumor (> 1 cm) and capsular invasion, are positively correlated with LN-prRLN metastasis. Our scoring system can help surgeons non-invasively determine which patients should undergo LN-prRLN resection before surgery. We recommend that LN-prRLN resection should be performed when the score is above 103.1.
How to Promote Energy Transition With Market Design: A Review on China’s Electric Power Sector
Authors: Pingkuo Liu , Pengbo Gao , Chen Zhang
Published: September 2021

Energy transition, especially in the power industry, will lead to a significant promotion in energy sustainable development. Lots of emphases have been focused on the impact of policy on the energy transition; however, there were little studies on the role of the market. This paper will be devoted to the theoretical basis of market design comprehensively and discusses the obstacles restricting China’s energy transition by using an Institution-Economics-Technology-Behavior (IETB) analysis framework (four dimensions including Institution, Economics, Technology, and Behavior). In addition, the paper provides an overview of research findings on some available market designs related to the energy transition. Of note, power spot market, power capacity market, power futures market, carbon emission market, and Tradable Green Certificate (TGC) market are highlighted and discussed with emphasis. And the effects of implementing each market on overcoming those obstacles in the energy transition process are analyzed. The review results show that the market design is as important as the policy-making; hence, it is unwise for energy transition to focus on policies and ignore markets, and the market design should be pertinent and objective. Finally, some policy recommendations and market design suggestions are put forward.
Cooperative Synthetic Inertia Control for Wind Farms Considering Frequency Regulation Capability
Authors: Shi Qiaoming , Liu Lei , Wang Yongping , Lu Yu , Zou Qiang , Zhang Qingwu , Liu Hongqing
Published: September 2021

To fully utilize the frequency regulation (FR) capability of wind turbines (WTs) and to avoid a secondary frequency drop caused by the rotor speed recovery, this paper firstly proposes an FR capability evaluation method for wind farms based on the principle of equal rotational kinetic energy of WTs, and analyses the essence of cooperative rotor speed recovery for WTs. Based on these, a cooperative synthetic inertia control (CSIC) for wind farms considering FR capability is proposed. By introducing the cooperative coefficient, the CSIC can fully utilize the FR capability of WTs, maintain the fast response of WTs with synthetic inertia control, and reduce communication requirements for the wind farm control center. By directly compensating the auxiliary FR power of WTs, the CSIC realizes the cooperative rotor speed recovery for WTs between different wind farms, avoiding a secondary frequency drop and a complex schedule of rotor speed recovery for multiple WTs. Finally, the simulation results verify the effectiveness and feasibility of the proposed control.
Why is Lake Urmia Drying up? Prognostic Modeling With Land-Use Data and Artificial Neural Network
Authors: Rahimi Akbar , Breuste Jürgen
Published: September 2021

Lake Urmia (LU) is considered as the largest salt water lake in Iran and has severe restrictions on water resources and becoming a salt lake increasingly. The LU drought will Couse ecological, health, social and economic problems. Land-use change and the increasing of salt areas evaluated in this work using satellite imagery. We evaluated the present situation and changes of the lake area in the past and further changes until 2025. The results indicated that from 1987 to 2000, the process of change has slowed down and less than 2% of the lake’s water area was reduced, and from 2000 to 2010, these shrinking processes were faster and more than 28% of the lake water area disappeared. The intensity of the shrinking from 2010 to 2014 is very severe. Using the Land Transformation Model, the continuation of the changes was modeled until 2025. The results of the modeling indicate the conversion of the water lake to salt lake in this period, and in the north part, the shallow waters occupy 0.7% of the total lake area. The result shows that climate change was not the significant factors for drying up of the lake but human factors such as building dams to store water for irrigation, increasing groundwater use by established deeper wells for agricultural irrigation were the important factors for drying. With changing of management of the waters leading to the lake and the transfer of new water resources to the lake between 2014 and 2016, the area of the lake increased to a double. It was evident that by proper planning and managing of water resources, the lake’s restoration can be achieved.
Effects of Acute and Chronic Exposure to Semicarbazide on the Sea Cucumber Apostichopus japonicus
Authors: Tian Xiuhui , Li Huanjun , Zhang Xiuzhen , Xu Yingjiang , Zhang Huawei , Han Dianfeng , Liu Huan , Wang Bin , Cui Yanmei , Liu Huihui , Zhou Quanli , Gong Xianghong
Published: September 2021

The effects of acute and chronic exposure to semicarbazide were carried out on the sea cucumber Apostichopus japonicus. A half-maximal lethal concentration of 3.72 g/L of semicarbazide hydrochloride (95% confidence interval 3.43–4.02 g/L) was deduced. At 20, 4, and 2% of the half-maximal lethal concentrations, a 28-days exposure induced morphological alterations, oxidative stress, and acetylcholinesterase (AChE) activity in the respiratory tree, intestinal tract, and longitudinal muscle of A. japonicus. Exposure to 20% of the half-maximal lethal concentration resulted in lesions in the respiratory tree and disintegration in the intestinal tract. Exposure to lower concentration induced a gradual accumulation of lesions in the respiratory tree, intestinal tract, and longitudinal muscle. Levels of markers of oxidative stress and neurotransmission, including superoxide dismutase (SOD), catalase, and AChE, were increased during the initial days of exposure and then decreased. The activity of SOD, catalase, and AChE were highest in A. japonicus exposed to 4%, followed by 20 and 2% of the half-maximal lethal concentration at the same time. At the later stages of the 28-days exposure, marker levels were decreased and close to levels in the control groups. Non-targeted metabolomics indicated that significantly different metabolites were screened out, 28 in the positive ion mode and 38 in the negative ion mode, impairments in neurological function, osmotic pressure regulation, energy metabolism, and protein digestion and absorption following exposure of A. japonicus to semicarbazide. KEGG pathway enrichment showed that the exposure affected pathways related to ABC transporters, central carbon metabolism in cancer, protein digestion and absorption, aminoacyl-tRNA biosynthesis, and biosynthesis of unsaturated fatty acids.
A New Global Ocean Climatology
Authors: Shahzadi Kanwal , Pinardi Nadia , Barth Alexander , Troupin Charles , Lyubartsev Vladyslav , Simoncelli Simona
Published: September 2021

A new global ocean temperature and salinity climatology is proposed for two time periods: a long time mean using multiple sensor data for the 1900–2017 period and a shorter time mean using only profiling float data for the 2003–2017 period. We use the historical database of World Ocean Database 2018. The estimation approach is novel as an additional quality control procedure is implemented, along with a new mapping algorithm based on Data Interpolating Variational Analysis. The new procedure, in addition to the traditional quality control approach, resulted in low sensitivity in terms of the first guess field choice. The roughness index and the root mean square of residuals are new indices applied to the selection of the free mapping parameters along with sensitivity experiments. Overall, the new estimates were consistent with previous climatologies, but several differences were found. The cause of these discrepancies is difficult to identify due to several differences in the procedures. To minimise these uncertainties, a multi-model ensemble mean is proposed as the least uncertain estimate of the global ocean temperature and salinity climatology.
Identification of Key Genes Associated With the Process of Hepatitis B Inflammation and Cancer Transformation by Integrated Bioinformatics Analysis
Authors: Zhang Jingyuan , Liu Xinkui , Zhou Wei , Lu Shan , Wu Chao , Wu Zhishan , Liu Runping , Li Xiaojiaoyang , Wu Jiarui , Liu Yingying , Guo Siyu , Jia Shanshan , Zhang Xiaomeng , Wang Miaomiao
Published: September 2021

Background

Hepatocellular carcinoma (HCC) has become the main cause of cancer death worldwide. More than half of hepatocellular carcinoma developed from hepatitis B virus infection (HBV). The purpose of this study is to find the key genes in the transformation process of liver inflammation and cancer and to inhibit the development of chronic inflammation and the transformation from disease to cancer.

Methods

Two groups of GEO data (including normal/HBV and HBV/HBV-HCC) were selected for differential expression analysis. The differential expression genes of HBV-HCC in TCGA were verified to coincide with the above genes to obtain overlapping genes. Then, functional enrichment analysis, modular analysis, and survival analysis were carried out on the key genes.

Results

We identified nine central genes (CDK1, MAD2L1, CCNA2, PTTG1, NEK2) that may be closely related to the transformation of hepatitis B. The survival and prognosis gene markers composed of PTTG1, MAD2L1, RRM2, TPX2, CDK1, NEK2, DEPDC1, and ZWINT were constructed, which performed well in predicting the overall survival rate.

Conclusion

The findings of this study have certain guiding significance for further research on the transformation of hepatitis B inflammatory cancer, inhibition of chronic inflammation, and molecular targeted therapy of cancer.
Epidemiology of Rare Hereditary Diseases in the European Part of Russia: Point and Cumulative Prevalence
Authors: Zinchenko Rena A. , Ginter Eugeny K. , Marakhonov Andrey V. , Petrova Nika V. , Kadyshev Vitaly V. , Vasilyeva Tatyana P. , Alexandrova Oksana U. , Polyakov Alexander V. , Kutsev Sergey I.
Published: September 2021

The issue of point prevalence, cumulative prevalence (CP), and burden of rare hereditary diseases (RHD), comprising 72–80% of the group of rare diseases, is discussed in many reports and is an urgent problem, which is associated with the rapid progress of genetic technology, the identification of thousands of genes, and the resulting problems in society. This work provides an epidemiological analysis of the groups of the most common RHDs (autosomal dominant, autosomal recessive, and X-linked) and their point prevalence (PP) and describes the structure of RHD diversity by medical areas in 14 spatially remote populations of the European part of Russia. The total size of the examined population is about 4 million. A total of 554 clinical forms of RHDs in 10,265 patients were diagnosed. The CP for all RHDs per sample examined was 277.21/100,000 (1:361 people). It is worth noting that now is the time for characterizing the accumulated data on the point prevalence of RHDs, which will help to systematize our knowledge and allow us to develop a strategy of care for patients with RHDs. However, it is necessary to address the issues of changing current medical classifications and coding systems for nosological forms of RHDs, which have not kept pace with genetic advances.
Construction of a Novel Gene-Based Model for Survival Prediction of Hepatitis B Virus Carriers With HCC Development
Authors: Huang Yuan , Tu Wen-Ling , Yao Yan-Qiu , Cai Ye-Ling , Ma Li-Ping
Published: September 2021

Despite the effectiveness of hepatitis B virus (HBV) vaccination in reducing the prevalence of chronic HBV infection as well as the incidence of acute hepatitis B, fulminant hepatitis, liver cirrhosis and hepatocellular carcinoma (HCC), there was still a large crowd of chronically infected populations at risk of developing cirrhosis or HCC. In this study, we established a comprehensive prognostic system covering multiple signatures to elevate the predictive accuracy for overall survival (OS) of hepatitis B virus carriers with HCC development. Weighted Gene Co-Expression Network Analysis (WGCNA), Least Absolute Shrinkage and Selection Operator (LASSO), Support Vector Machine Recursive Feature Elimination (SVM-RFE), and multivariate COX analysis, along with a suite of other online analyses were successfully applied to filtrate a three-gene signature model (TP53, CFL1, and UBA1). Afterward, the gene-based risk score was calculated based on the Cox coefficient of the individual gene, and the prognostic power was assessed by time-dependent receiver operating characteristic (tROC) and Kaplan–Meier (KM) survival analysis. Furthermore, the predictive power of the nomogram, integrated with the risk score and clinical parameters (age at diagnosis and TNM stage), was revealed by the calibration plot and tROC curves, which was verified in the validation set. Taken together, our study may be more effective in guiding the clinical decision-making of personalized treatment for HBV carriers.
Tumor NLRP3-Derived IL-1β Drives the IL-6/STAT3 Axis Resulting in Sustained MDSC-Mediated Immunosuppression
Authors: Tengesdal Isak W. , Dinarello Alberto , Powers Nicholas E. , Burchill Matthew A. , Joosten Leo A. B. , Marchetti Carlo , Dinarello Charles A.
Published: September 2021

Tumors evade the immune system by inducing inflammation. In melanoma, tumor-derived IL-1β drives inflammation and the expansion of highly immunosuppressive myeloid-derived suppressor cells (MDSCs). Similar in many tumors, melanoma is also linked to the downstream IL‐6/STAT3 axis. In this study, we observed that both recombinant and tumor-derived IL-1β specifically induce pSTAT3(Y705), creating a tumor-autoinflammatory loop, which amplifies IL-6 signaling in the human melanoma cell line 1205Lu. To disrupt IL-1β/IL-6/STAT3 axis, we suppressed IL-1β-mediated inflammation by inhibiting the NOD-like receptor protein 3 (NLRP3) using OLT1177, a safe-in-humans specific NLRP3 oral inhibitor.In vivo, using B16F10 melanoma, OLT1177 effectively reduced tumor progression (p< 0.01); in primary tumors, OLT1177 decreased pSTAT3(Y705) by 82% (p<0.01) andII6expression by 53% (p<0.05). Disruption of tumor-derived NLRP3, either pharmacologically or genetically, reduced STAT3 signaling in bone marrow cells. In PMN-MDSCs isolated from tumor-bearing mice treated with OLT1177, we observed significant reductions in immunosuppressive genes such asPdcd1l1,Arg1,Il10andTgfb1. In conclusion, the data presented here show that the inhibition of NLRP3 reduces IL-1β induction of pSTAT3(Y705) preventing expression of immunosuppressive genes as well as activity in PMN-MDSCs.
N6-Methyladenosine in Cancer Immunotherapy: An Undervalued Therapeutic Target
Authors: Quan Chao , Belaydi Othmane , Hu Jiao , Li Huihuang , Yu Anze , Liu Peihua , Yi Zhenglin , Qiu Dongxu , Ren Wenbiao , Ma Hongzhi , Gong Guanghui , Ou Zhenyu , Chen Minfeng , Sun Yin , Chen Jinbo , Zu Xiongbing
Published: September 2021

N6-methylation of adenosine (m6A), a post-transcriptional regulatory mechanism, is the most abundant nucleotide modification in almost all types of RNAs. The biological function of m6A in regulating the expression of oncogenes or tumor suppressor genes has been widely investigated in various cancers. However, recent studies have addressed a new role of m6A modification in the anti-tumor immune response. By modulating the fate of targeted RNA, m6A affects tumor-associated immune cell activation and infiltration in the tumor microenvironment (TME). In addition, m6A-targeting is found to affect the efficacy of classical immunotherapy, which makes m6A a potential target for immunotherapy. Although m6A modification together with its regulators may play the exact opposite role in different tumor types, targeting m6A regulators has been shown to have wide implications in several cancers. In this review, we discussed the link between m6A modification and tumor with an emphasis on the importance of m6A in anti-tumor immune response and immunotherapy.
Partially Hydrolysed Whey Has Superior Allergy Preventive Capacity Compared to Intact Whey Regardless of Amoxicillin Administration in Brown Norway Rats
Authors: Graversen Katrine Bækby , Larsen Jeppe Madura , Pedersen Signe Schultz , Sørensen Laila Vestergaard , Christoffersen Heidi Frahm , Jacobsen Lotte Neergaard , Halken Susanne , Licht Tine Rask , Bahl Martin Iain , Bøgh Katrine Lindholm
Published: September 2021

Background

It remains largely unknown how physicochemical properties of hydrolysed infant formulas influence their allergy preventive capacity, and results from clinical and animal studies comparing the preventive capacity of hydrolysed infant formula with conventional infant formula are inconclusive. Thus, the use of hydrolysed infant formula for allergy prevention in atopy-prone infants is highly debated. Furthermore, knowledge on how gut microbiota influences allergy prevention remains scarce.

Objective

To gain knowledge on (1) how physicochemical properties of hydrolysed whey products influence the allergy preventive capacity, (2) whether host microbiota disturbance influences allergy prevention, and (3) to what extent hydrolysed whey products influence gut microbiota composition.

Methods

The preventive capacity of four different ad libitum administered whey products was investigated in Brown Norway rats with either a conventional or an amoxicillin-disturbed gut microbiota. The preventive capacity of products was evaluated as the capacity to reduce whey-specific sensitisation and allergic reactions to intact whey after intraperitoneal post-immunisations with intact whey. Additionally, the direct effect of the whey products on the growth of gut bacteria derived from healthy human infant donors was evaluated by in vitro incubation.

Results

Two partially hydrolysed whey products with different physicochemical characteristics were found to be superior in preventing whey-specific sensitisation compared to intact and extensively hydrolysed whey products. Daily oral amoxicillin administration, initiated one week prior to intervention with whey products, disturbed the gut microbiota but did not impair the prevention of whey-specific sensitisation. The in vitro incubation of infant faecal samples with whey products indicated that partially hydrolysed whey products might confer a selective advantage to enterococci.

Conclusions

Our results support the use of partially hydrolysed whey products for prevention of cow’s milk allergy in atopy-predisposed infants regardless of their microbiota status. However, possible direct effects of partially hydrolysed whey products on gut microbiota composition warrants further investigation.
Obesity Enhances Disease Severity in Female Mice Following West Nile Virus Infection
Authors: Geerling Elizabeth , Stone E. Taylor , Steffen Tara L. , Hassert Mariah , Brien James D. , Pinto Amelia K.
Published: September 2021

A rise in adiposity in the United States has resulted in more than 70% of adults being overweight or obese, and global obesity rates have tripled since 1975. Following the 2009 H1N1 pandemic, obesity was characterized as a risk factor that could predict severe infection outcomes to viral infection. Amidst the SARS-CoV-2 pandemic, obesity has remained a significant risk factor for severe viral disease as obese patients have a higher likelihood for developing severe symptoms and requiring hospitalization. However, the mechanism by which obesity enhances viral disease is unknown. In this study, we utilized a diet-induced obesity mouse model of West Nile virus (WNV) infection, a flavivirus that cycles between birds and mosquitoes and incidentally infects both humans and mice. Likelihood for severe WNV disease is associated with risk factors such as diabetes that are comorbidities also linked to obesity. Utilizing this model, we showed that obesity-associated chronic inflammation increased viral disease severity as obese female mice displayed higher mortality rates and elevated viral titers in the central nervous system. In addition, our studies highlighted that obesity also dysregulates host acute adaptive immune responses, as obese female mice displayed significant dysfunction in neutralizing antibody function. These studies highlight that obesity-induced immunological dysfunction begins at early time points post infection and is sustained through memory phase, thus illuminating a potential for obesity to alter the differentiation landscape of adaptive immune cells.
Long-Term Trends and Impact of SARS-CoV-2 COVID-19 Lockdown on the Primary Productivity of the North Indian Ocean
Authors: Sunanda N. , Kuttippurath J. , Peter R. , Chakraborty Kunal , Chakraborty A.
Published: September 2021

COrona VIrus Disease (COVID) 2019 pandemic forced most countries to go into complete lockdown and India went on complete lockdown from 24th March 2020 to 8th June 2020. To understand the possible implications of lockdown, we analyze the long-term distribution of Net Primary Productivity (NPP) in the North Indian Ocean (NIO) and the factors that influence NPP directly and indirectly, for the period 2003–2019 and 2020 separately. There exists a seasonal cycle in the relationship between Aerosol Optical Depth (AOD), Chlorophyll-a (Chl-a) and NPP in agreement with the seasonal transport of aerosols and dust into these oceanic regions. In Arabian Sea (AS), the highest Chl-a (0.58 mg/m3), NPP (696.57 mg/C/m2/day) and AOD (0.39) are observed in June, July, August, and September (JJAS). Similarly, maximum Chl-a (0.48 mg/m3) and NPP (486.39 mg/C/m2/day) are found in JJAS and AOD (0.27) in March, April, and May (MAM) in Bay of Bengal. The interannual variability of Chl-a and NPP with wind speed and Sea Surface Temperature (SST) is also examined, where the former has a positive and the latter has a negative feedback to NPP. The interannual variability of NPP reveals a decreasing trend in NPP, which is interlinked with the increasing trend in SST and AOD. The analysis of wind, SST, Chl-a, and AOD for the pre-lockdown, lockdown, and post lockdown periods of 2020 is employed to understand the impact of COVID-19 lockdown on NPP. The assessment shows the reduction in AOD, decreased wind speeds, increased SST and reduced NPP during the lockdown period as compared to the pre-lockdown, post-lockdown and climatology. This analysis is expected to help to understand the impact of aerosols on the ocean biogeochemistry, nutrient cycles in the ocean biogeochemical models, and to study the effects of climate change on ocean ecosystems.
A Biophysical Model and Network Analysis of Invertebrate Community Dispersal Reveals Regional Patterns of Seagrass Habitat Connectivity
Authors: Cristiani John , Rubidge Emily , Forbes Coreen , Moore-Maley Ben , O’Connor Mary I.
Published: September 2021

The dispersal of marine organisms is a critical process for the maintenance of biodiversity and ecosystem functioning across a seascape. Understanding the patterns of habitat connectivity that arise from the movement of multiple species can highlight the role of regional processes in maintaining local community structure. However, quantifying the probability and scale of dispersal for marine organisms remains a challenge. Here, we use a biophysical model to simulate dispersal, and we conduct a network analysis to predict connectivity patterns across scales for the community of invertebrates associated with seagrass habitat in British Columbia, Canada. We found many possible connections and few isolated habitat meadows, but the probability of most connections was low. Most habitat connections occurred within 3 days of dispersal time over short distances, indicating potential limits to long distance dispersal and little effect of species-specific dispersal abilities on the potential spatial extent of habitat connectivity. We then highlight the different roles that individual seagrass meadows can play in maintaining network connectivity. We also identify clusters of connected meadows and use these clusters to estimate the spatial scale of community dynamics. The connectivity patterns generated by our dispersal simulations highlight the importance of considering marine communities in their broad seascape context, with applications for the prioritization and conservation of habitat that maintains connectivity.
Prediction of Radiation Pneumonitis Using Genome-Scale Flux Analysis of RNA-Seq Derived From Peripheral Blood
Authors: Yang Siqi , Yao Yi , Dong Yi , Liu Junqi , Li Yingge , Yi Lina , Huang Yani , Gao Yanjun , Yin Junping , Li Qingqing , Ye Dafu , Gong Hongyun , Xu Bin , Li Jian , Song Qibin
Published: September 2021

Purpose: Radiation pneumonitis (RP) frequently occurs during a treatment course of chest radiotherapy, which significantly reduces the clinical outcome and efficacy of radiotherapy. The ability to easily predict RP before radiotherapy would allow this disease to be avoided.

Methods and Materials: This study recruited 48 lung cancer patients requiring chest radiotherapy. For each participant, RNA sequencing (RNA-Seq) was performed on a peripheral blood sample before radiotherapy. The RNA-Seq data was then integrated into a genome-scale flux analysis to develop an RP scoring system for predicting the probability of occurrence of RP. Meanwhile, the clinical information and radiation dosimetric parameters of this cohort were collected for analysis of any statistical associations between these parameters and RP. A non-parametric rank sum test showed no significant difference between the predicted results from the RP score system and the clinically observed occurrence of RP in this cohort.

Results: The results of the univariant analysis suggested that the tumor stage, exposure dose, and bilateral lung dose of V5 and V20 were significantly associated with the occurrence of RP. The results of the multivariant analysis suggested that the exposure doses of V5 and V20 were independent risk factors associated with RP and a level of RP ≥ 2, respectively. Thus, our results indicate that our RP scoring system could be applied to accurately predict the risk of RP before radiotherapy because the scores were highly consistent with the clinically observed occurrence of RP.

Conclusion: Compared with the standard statistical methods, this genome-scale flux-based scoring system is more accurate, straightforward, and economical, and could therefore be of great significance when making clinical decisions for chest radiotherapy.
The Role of Type II Fatty Acid Synthesis Enzymes FabZ, ODSCI, and ODSCII in the Pathogenesis of Toxoplasma gondii Infection
Authors: Xu Xiao-Pei , Elsheikha Hany M. , Liu Wen-Ge , Zhang Zhi-Wei , Sun Li-Xiu , Liang Qin-Li , Song Ming-Xin , Zhu Xing-Quan
Published: September 2021

Toxoplasma gondii is an obligate intracellular protozoan parasite, which has a worldwide distribution and can infect a large number of warm-blooded animals and humans. T. gondii must colonize and proliferate inside the host cells in order to maintain its own survival by securing essential nutrients for the development of the newly generated tachyzoites. The type II fatty acid biosynthesis pathway (FASII) in the apicoplast is essential for the growth and survival of T. gondii. We investigated whether deletion of genes in the FASII pathway influences the in vitro growth and in vivo virulence of T. gondii. We focused on beta-hydroxyacyl-acyl carrier protein dehydratase (FabZ) and oxidoreductase, short chain dehydrogenase/reductase family proteins ODSCI and ODSCII. We constructed T. gondii strains deficient in FabZ, ODSCI, and ODSCII using CRISPR-Cas9 gene editing technology. The results of immunofluorescence assay, plaque assay, proliferation assay and egress assay showed that in RHΔFabZ strain the apicoplast was partly lost and the growth ability of the parasite in vitro was significantly inhibited, while for RHΔODSCI and RHΔODSCII mutant strains no similar changes were detected. RHΔFabZ exhibited reduced virulence for mice compared with RHΔODSCI and RHΔODSCII, as shown by the improved survival rate. Deletion of FabZ in the PRU strain significantly decreased the brain cyst burden in mice compared with PRUΔODSCI and PRUΔODSCII. Collectively, these findings suggest that FabZ contributes to the growth and virulence of T. gondii, while ODSCI and ODSCII do not contribute to these traits.
Whole-Genome Sequencing of Brachyspira hyodysenteriae Isolates From England and Wales Reveals Similarities to European Isolates and Mutations Associated With Reduced Sensitivity to Antimicrobials
Authors: Stubberfield Emma , Sheldon Jonathan , Card Roderick M. , AbuOun Manal , Rogers Jon , Williamson Susanna , Kay Gemma L. , Pallen Mark J. , Anjum Muna F.
Published: September 2021

Brachyspira hyodysenteriae is the principal cause of swine dysentery, a disease that threatens economic productivity of pigs in many countries as it can spread readily within and between farms, and only a small number of antimicrobials are authorized for treatment of pigs. In this study, we performed whole-genome sequencing (WGS) of 81 B. hyodysenteriae archived at the Animal and Plant Health Agency (APHA) from diagnostic submissions and herd monitoring in England and Wales between 2004 and 2015. The resulting genome sequences were analyzed alongside 34 genomes we previously published. Multi-locus sequence typing (MLST) showed a diverse population with 32 sequence types (STs) among the 115 APHA isolates, 25 of them identified only in England; while also confirming that the dominant European clonal complexes, CC8 and CC52, were common in the United Kingdom. A core-genome SNP tree typically clustered the isolates by ST, with isolates from some STs detected only within a specific region in England, although others were more widespread, suggesting transmission between different regions. Also, some STs were more conserved in their core genome than others, despite these isolates being from different holdings, regions and years. Minimum inhibitory concentrations to commonly used antimicrobials (Tiamulin, Valnemulin, Doxycycline, Lincomycin, Tylosin, Tylvalosin) were determined for 82 of the genome-sequenced isolates; genomic analysis revealed mutations generally correlated well with the corresponding resistance phenotype. There was a major swine dysentery intervention program in 2009–2010, and antimicrobial survival curves showed a significant reduction in sensitivity to tiamulin and valnemulin in isolates collected in and after 2010, compared to earlier isolates. This correlated with a significant increase in post-2009 isolates harboring the pleuromutilin resistance gene tva(A), which if present, may facilitate higher levels of resistance. The reduction in susceptibility of Brachyspira from diagnostic submissions to pleuromutilins, emphasizes the need for prudent treatment, control and eradication strategies.
Uncovering Diagnostic Value of Mitogenome for Identification of Cryptic Species Fusarium graminearum Sensu Stricto
Authors: Wyrębek Joanna , Molcan Tomasz , Myszczyński Kamil , van Diepeningen Anne D. , Stakheev Alexander A. , Żelechowski Maciej , Bilska Katarzyna , Kulik Tomasz
Published: September 2021

Fungal complexes are often composed of morphologically nearly indistinguishable species with high genetic similarity. However, despite their close relationship, they can exhibit distinct phenotypic differences in pathogenicity and production of mycotoxins. Many plant pathogenic and toxigenic fungi have been shown to consist of such cryptic species. Identification of cryptic species in economically important pathogens has added value in epidemiologic studies and provides opportunities for better control. Analysis of mitochondrial genomes or mitogenomics opens up dimensions for improved diagnostics of fungi, especially when efficient recovery of DNA is problematic. In comparison to nuclear DNA, mitochondrial DNA (mtDNA) can be amplified with improved efficacy due to its multi-copy nature. However, to date, only a few studies have demonstrated the usefulness of mtDNA for identification of cryptic species within fungal complexes. In this study, we explored the value of mtDNA for identification of one of the most important cereal pathogens Fusarium graminearum sensu stricto (F.g.). We found that homing endonucleases (HEGs), which are widely distributed in mitogenomes of fungi, display small indel polymorphism, proven to be potentially species specific. The resulting small differences in their lengths may facilitate further differentiation of F.g. from the other cryptic species belonging to F. graminearum species complex. We also explored the value of SNP analysis of the mitogenome for typing F.g. The success in identifying F.g. strains was estimated at 96%, making this tool an attractive complement to other techniques for identification of F.g.
Harringtonine Inhibits Herpes Simplex Virus Type 1 Infection by Reducing Herpes Virus Entry Mediator Expression
Authors: Liu Ye , You Qiao , Zhang Fang , Chen Deyan , Huang Zhenping , Wu Zhiwei
Published: September 2021

Herpes simplex virus type 1 (HSV-1) infection induces various clinical disorders, such as herpes simplex encephalitis (HSE), herpes simplex keratitis (HSK), and genital herpes. In clinical intervention, acyclovir (ACV) is the major therapeutic drug used to suppress HSV-1; however, ACV-resistant strains have gradually increased. In the present study, harringtonine (HT) significantly inhibited infection of HSV-1 as well as two ACV-resistant strains, including HSV-1 blue and HSV-1 153. Time-of-drug addition assay further revealed that HT mainly reduced the early stage of HSV-1 infection. We also demonstrated that HT mainly affected herpes virus entry mediator (HVEM) expression as shown by qPCR, Western Blot, and Immunofluorescence. Collectively, HT showed antiviral activity against HSV-1 and ACV-resistant strains by targeting HVEM and could be a promising therapeutic candidate for mitigating HSV-1-induced-pathogenesis.
The Cerebrospinal Fluid Profile of Cholesterol Metabolites in Parkinson’s Disease and Their Association With Disease State and Clinical Features
Authors: Griffiths William J. , Abdel-Khalik Jonas , Moore Sarah F. , Wijeyekoon Ruwani S. , Crick Peter J. , Yutuc Eylan , Farrell Krista , Breen David P. , Williams-Gray Caroline H. , Theofilopoulos Spyridon , Arenas Ernest , Trupp Miles , Barker Roger A. , Wang Yuqin
Published: September 2021

Disordered cholesterol metabolism is linked to neurodegeneration. In this study we investigated the profile of cholesterol metabolites found in the cerebrospinal fluid (CSF) of Parkinson’s disease (PD) patients. When adjustments were made for confounding variables of age and sex, 7α,(25R)26-dihydroxycholesterol and a second oxysterol 7α,x,y-trihydroxycholest-4-en-3-one (7α,x,y-triHCO), whose exact structure is unknown, were found to be significantly elevated in PD CSF. The likely location of the additional hydroxy groups on the second oxysterol are on the sterol side-chain. We found that CSF 7α-hydroxycholesterol levels correlated positively with depression in PD patients, while two presumptively identified cholestenoic acids correlated negatively with depression.
Efficacy of Δ9 -Tetrahydrocannabinol (THC) Alone or in Combination With a 1:1 Ratio of Cannabidiol (CBD) in Reversing the Spatial Learning Deficits in Old Mice
Authors: Nidadavolu Prakash , Bilkei-Gorzo Andras , Krämer Michael , Schürmann Britta , Palmisano Michela , Beins Eva C. , Madea Burkhard , Zimmer Andreas
Published: September 2021

Decline in cognitive performance, an aspect of the normal aging process, is influenced by the endocannabinoid system (ECS). Cannabinoid receptor 1 (CB1) signaling diminishes with advancing age in specific brain regions that regulate learning and memory and abolishing CB1 receptor signaling accelerates cognitive aging in mice. We recently demonstrated that prolonged exposure to low dose (3 mg/kg/day) Δ9-tetrahydrocannabinol (THC) improved the cognitive performances in old mice on par with young untreated mice. Here we investigated the potential influence of cannabidiol (CBD) on this THC effect, because preclinical and clinical studies indicate that the combination of THC and CBD often exhibits an enhanced therapeutic effect compared to THC alone. We first tested the effectiveness of a lower dose (1 mg/kg/day) THC, and then the efficacy of the combination of THC and CBD in 1:1 ratio, same as in the clinically approved medicine Sativex®. Our findings reveal that a 1 mg/kg/day THC dose still effectively improved spatial learning in aged mice. However, a 1:1 combination of THC and CBD failed to do so. The presence of CBD induced temporal changes in THC metabolism ensuing in a transient elevation of blood THC levels. However, as CBD metabolizes, the inhibitory effect on THC metabolism was alleviated, causing a rapid clearance of THC. Thus, the beneficial effects of THC seemed to wane off more swiftly in the presence of CBD, due to these metabolic effects. The findings indicate that THC-treatment alone is more efficient to improve spatial learning in aged mice than the 1:1 combination of THC and CBD.