bluuebunny/crossref_metadata_2025 huggingface dataset:
Maternal high-fat diet decreases milk endocannabinoids with sex-specific changes in the cannabinoid and dopamine signaling and food preference in rat offspring
Authors: Dias-Rocha Camilla P. , Costa Julia C. B. , Oliveira Yamara S. , Fassarella Larissa B. , Woyames Juliana , Atella Georgia C. , Santos Gustavo R. C. , Pereira Henrique M. G. , Pazos-Moura Carmen C. , Almeida Mariana M. , Trevenzoli Isis H.
Published: March 2023

Introduction

Maternal high-fat (HF) diet during gestation and lactation programs obesity in rat offspring associated with sex-dependent and tissue-specific changes of the endocannabinoid system (ECS). The ECS activation induces food intake and preference for fat as well as lipogenesis. We hypothesized that maternal HF diet would increase the lipid endocannabinoid levels in breast milk programming cannabinoid and dopamine signaling and food preference in rat offspring.

Methods

Female Wistar rats were assigned into two experimental groups: control group (C), which received a standard diet (10% fat), or HF group, which received a high-fat diet (29% fat) for 8 weeks before mating and during gestation and lactation. Milk samples were collected to measure endocannabinoids and fatty acids by mass spectrometry. Cannabinoid and dopamine signaling were evaluated in the nucleus accumbens (NAc) of male and female weanling offspring. C and HF offspring received C diet after weaning and food preference was assessed in adolescence.

Results

Maternal HF diet reduced the milk content of anandamide (AEA) (p<0.05) and 2-arachidonoylglycerol (2-AG) (p<0.05). In parallel, maternal HF diet increased adiposity in male (p<0.05) and female offspring (p<0.05) at weaning. Maternal HF diet increased cannabinoid and dopamine signaling in the NAc only in male offspring (p<0.05), which was associated with higher preference for fat in adolescence (p<0.05).

Conclusion

Contrary to our hypothesis, maternal HF diet reduced AEA and 2-AG in breast milk. We speculate that decreased endocannabinoid exposure during lactation may induce sex-dependent adaptive changes of the cannabinoid-dopamine crosstalk signaling in the developing NAc, contributing to alterations in neurodevelopment and programming of preference for fat in adolescent male offspring.
Diabetes and intervertebral disc degeneration: A Mendelian randomization study
Authors: Jin Peihao , Xing Yonggang , Xiao Bin , Wei Yi , Yan Kai , Zhao Jingwei , Tian Wei
Published: March 2023

Introduction

Intervertebral disc degeneration (IVDD) is an important contributor of low back pain, which represents one of the most disabling symptoms within the adult population. Recently, increasing evidence suggests the potential association between Type 2 diabetes mellitus (T2DM) and IVDD. However, the causal relationship between these two common diseases remains unclear.

Methods

We conducted a two-sample Mendelian randomization (MR) analysis to assess the causal association between T2DM and IVDD. Sensitivity analysis was performed to test for heterogeneity and horizontal pleiotropy. Multivariable MR was also conducted to adjust for the effect of BMI on IVDD.

Results

A total of 128 independent single-nucleotide polymorphisms (SNPs) that were significantly associated with T2DM were selected as instrumental variables in univariable MR analysis. Our results showed that patients with T2DM had a higher risk of developing IVDD (OR, 1.069; 95% CI, 1.026–1.115; p = 0.002). The relationship remained stable in sensitive analysis including multivariable MR, which implicated the direct causal effect of T2DM on IVDD (OR, 1.080; 95% CI, 1.041–1.121; p < 0.001) after adjusting for BMI.

Conclusions

MR analysis indicated a causal effect of T2DM on IVDD, and the effect persisted even when we accounted for the impact of BMI.
Fibroblast growth factor 21 and prognosis of patients with cardiovascular disease: A meta-analysis
Authors: Yan Bing , Ma Sicong , Yan Chenghui , Han Yaling
Published: March 2023

Background

The role of fibroblast growth factor 21 (FGF21) in predicting the long-term prognosis of patients with cardiovascular disease (CVD) remains unknown.

Methods

A comprehensive search in PubMed, Embase, and the Cochrane Library was performed to identify studies reporting the association between FGF21 and prognosis among patients with CVD. A meta-analysis was performed, with patients stratified by coronary artery disease (CAD) or heart failure (HF). The endpoint of CAD or HF was major adverse cardiovascular events defined by each study and a composite of death or HF readmission, respectively. The I2 method and linear regression test of funnel plot asymmetry were used to test heterogeneity (I2 > 50% indicates substantial heterogeneity) and publication bias (asymmetry P < 0.05, indicating publication bias).

Results

A total of 807 records were retrieved, and nine studies were finally included. Higher FGF21 levels were significantly associated with the risk of major adverse cardiovascular events in patients with CAD (multivariate hazard ratio [HR]: 1.77, 95% confidence interval [CI]: 1.40–2.23, P < 0.05, I2 = 0%, fixed-effect model). Increased FGF21 levels were also associated with the risk of all-cause death among patients with CAD (multivariate HR: 2.67, 95% CI: 1.25–5.72, P < 0.05, I2 = 64%, random-effect model). No association was found between FGF21 and the endpoint among patients with HF (HR: 1.57, 95% CI: 0.99–2.48, P > 0.05, random-effect model), but a large heterogeneity (I2 = 95%) and potential publication bias (Asymmetry P < 0.05) existed in the analysis.

Conclusion

Increased FGF21 levels were independently associated with poor prognosis of CAD, whereas the role of FGF21 in predicting clinical outcomes of HF requires further investigation.
Identifying the challenges and opportunities of PCOS awareness month by analysing its global digital impact
Authors: Malhotra Kashish , Pan Carina Synn Cuen , Davitadze Meri ,   Team PCOS SEva, Kempegowda Punith
Published: March 2023

Background and objective

Although significant resources are invested each September for PCOS Awareness Month campaign, there are no studies measuring its impact. We evaluated the digital impact of PCOS Awareness Month, common themes and associated topics, top influencers, and global equity of influence during the PCOS Awareness month.

Methods

In this serial cross-sectional analysis, we studied the outputs from Symplur® to study the total impressions of #PCOS on Twitter®. We tracked the hashtags—#PCOS, #PCOSawarenessmonth, #PCOSawareness—and a search query— “#PCOS OR #PCOSawarenessmonth OR #PCOSawareness”—using Sproutsocial® to study the total number of tweets related to PCOS Awareness Month. Network analysis was done using SocioViz® to identify common themes and associated topics. Using SymplurRank® machine learning algorithm, the top 10 #PCOS influencers were identified based on the number of mentions received. Google® Trends was used to study the web and news search popularity over the last 10 years beyond social media platforms.

Results

An overall upward trend in the digital impact of PCOS awareness was noted since 2017. While the top themes associated with PCOS (insulin resistance, depression, anxiety, menopause, hormones, infertility) remained the same in 2021 and 2022, newer themes emerged in the latter year suggesting the need for ongoing review. News outlets were the most influential organisations during PCOS Awareness Month in both years of study. Seven of the top 10 users were the same in both years. Limited engagement from African, Asian, South American, and non-English speaking European countries was seen on Google Trends analysis.

Conclusion

Active involvement from various stakeholders of PCOS Awareness Month has shaped it into an effective strategy to raise awareness with social media playing a crucial role in amplifying the message. Our findings also provide an opportunity to understand the current perceptions and expectations amongst the public, which can influence future healthcare investment and research.
Effects of Ureaplasma urealyticum infection on semen quality and sperm morphology
Authors: Xianchun Fu , Jun Fang , Zhijun Dai , Mingyun Hong
Published: March 2023

Introduction

Ureaplasma urealyticum (U. urealyticum) infection is primarily associated with damage to male fertility through its effects on male sperm parameters. However, its effects on sperm semiological variables remain unclear. Therefore, this study aimed to investigate whether U. urealyticum infection was associated with semen quality and sperm morphology.

Methods

From 2019 to 2021, this cross-sectional study analyzed infective pathogens and semen variables in 1064 males (22–30 years old) recruited from our reproductive center and the general public. Routine semen parameters and normal sperm morphology rate were analyzed using methods outlined by the World Health Organization. The associations between semen quality, sperm morphology, and U. urealyticum infection were studied using general linear models.

Results

The participants were categorized into three groups: (i) U. urealyticum infection (n=328), (ii) non-U. urealyticum infection (including males with urogenital tract infection symptoms but no U. urealyticum detected in their semen samples, n=377), and (iii) normal volunteers (males without symptoms of urogenital tract infection and no pathogens detected in semen samples, n=359). U. urealyticum in semen samples was observed to be associated with lower sperm concentrations (p<0.001) and a lower ratio of anterograde motile spermatozoa (p<0.001). Semen cultures positive for U. urealyticum were associated with lower normal sperm morphology (p<0.001) compared to semen cultures negative for U. urealyticum.

Conclusion

This study shows the importance of proper investigations for U. urealyticum during routine clinical examinations and diagnoses of males with infertility.
Trends of national and sub-national burden attributed to kidney dysfunction risk factor in Iran: 1990-2019
Authors: Nejadghaderi Seyed Aria , Saeedi Moghaddam Sahar , Keykhaei Mohammad , Shobeiri Parnian , Rezaei Negar , Rezaei Nazila ,   GBD 2019 Iran Kidney Dysfunction Collaborators, Naghavi Mohsen , Larijani Bagher , Farzadfar Farshad
Published: March 2023

Background

Kidney dysfunction is a risk factor for cardiovascular disease and chronic kidney disease. Herein, we aimed to describe the attributable burden of kidney dysfunction at the national and sub-national levels in Iran.

Methods

The Global Burden of Disease (GBD) 2019 data were extracted on the deaths, disability-adjusted life years (DALYs), years of life lost, and years lived with disability attributed to the risk factor of kidney dysfunction by age and sex at the national and provincial levels from 1990-2019. Also, risk exposure was reported by summary exposure value (SEV) with a range of 0 to 100. The estimated values were based on a comparative risk assessment framework.

Results

In 2019, the age-standardized death rate and age-standardized DALYs rate attributable to kidney dysfunction were 58.2 (95% uncertainty interval of 48.8-68.1) and 1127.2 (981.1-1282.7) per 100,000 population in Iran, respectively. Also, the Sistan and Baluchistan province (1729.3 [1478.3-2006.4]) and the province of Tehran (681.9 [571.4-809.8]) had the greatest and lowest age-standardized DALYs rates, respectively. Nationally, SEVs increased from 22.8 to 26.2. The age-standardized burden attributable to kidney dysfunction had a positive association with age advancement. The attributable age-standardized deaths and DALYs rates in all socio-demographic index regions decreased from 1990-2019. Also, the highest and lowest attributable age-standardized DALYs rates of kidney dysfunction came from ischemic heart disease and peripheral artery disease in 2019, respectively.

Conclusion

Although the attributed age-standardized DALYs and death rates decreased from 1990-2019, risk exposure increased and remains a crucial risk factor in Iran. Therefore, policymakers should consider preparing a preventive program that takes into account different levels of prevention of kidney dysfunction.
Epigenetic control of mesenchymal stem cells orchestrates bone regeneration
Authors: Wang Xiaofeng , Yu Fanyuan , Ye Ling
Published: March 2023

Recent studies have revealed the vital role of MSCs in bone regeneration. In both self-healing bone regeneration processes and biomaterial-induced healing of bone defects beyond the critical size, MSCs show several functions, including osteogenic differentiation and thus providing seed cells. However, adverse factors such as drug intake and body senescence can significantly affect the functions of MSCs in bone regeneration. Currently, several modalities have been developed to regulate MSCs’ phenotype and promote the bone regeneration process. Epigenetic regulation has received much attention because of its heritable nature. Indeed, epigenetic regulation of MSCs is involved in the pathogenesis of a variety of disorders of bone metabolism. Moreover, studies using epigenetic regulation to treat diseases are also being reported. At the same time, the effects of epigenetic regulation on MSCs are yet to be fully understood. This review focuses on recent advances in the effects of epigenetic regulation on osteogenic differentiation, proliferation, and cellular senescence in MSCs. We intend to illustrate how epigenetic regulation of MSCs orchestrates the process of bone regeneration.
A standardized extract of Coleus forskohlii root protects rats from ovariectomy-induced loss of bone mass and strength, and impaired bone material by osteogenic and anti-resorptive mechanisms
Authors: Kulkarni Chirag , Sharma Shivani , Porwal Konica , Rajput Swati , Sadhukhan Sreyanko , Singh Vaishnavi , Singh Akanksha , Baranwal Sanjana , Kumar Saroj , Girme Aboli , Pandey Alka Raj , Singh Suriya Pratap , Sashidhara Koneni V. , Kumar Navin , Hingorani Lal , Chattopadhyay Naibedya
Published: March 2023

Introduction

In obese humans, Coleus forskohlii root extract (CF) protects against weight gain owing to the presence of forskolin, an adenylate cyclase (AC) activator. As AC increases intracellular cyclic adenosine monophosphate (cAMP) levels in osteoblasts that has an osteogenic effect, we thus tested the skeletal effects of a standardized CF (CFE) in rats.

Methods

Concentrations of forskolin and isoforskolin were measured in CFE by HPLC. CFE and forskolin (the most abundant compound present in CFE) were studied for their osteogenic efficacy in vitro by alkaline phosphatase (ALP), cAMP and cyclic guanosine monophosphate (cGMP) assays. Femur osteotomy model was used to determine the osteogenic dose of CFE. In growing rats, CFE was tested for its osteogenic effect in intact bone. In adult ovariectomized (OVX) rats, we assessed the effect of CFE on bone mass, strength and material. The effect of forskolin was assessed in vivo by measuring the expression of osteogenic genes in the calvarium of rat pups.

Results

Forskolin content in CFE was 20.969%. CFE increased osteoblast differentiation and intracellular cAMP and cGMP levels in rat calvarial osteoblasts. At 25 mg/kg (half of human equivalent dose), CFE significantly enhanced calcein deposition at the osteotomy site. In growing rats, CFE promoted modeling-directed bone formation. In OVX rats, CFE maintained bone mass and microarchitecture to the level of sham-operated rats. Moreover, surface-referent bone formation in CFE treated rats was significantly increased over the OVX group and was comparable with the sham group. CFE also increased the pro-collagen type-I N-terminal propeptide: cross-linked C-telopeptide of type-I collagen (PINP : CTX-1) ratio over the OVX rats, and maintained it to the sham level. CFE treatment decreased the OVX-induced increases in the carbonate-to-phosphate, and carbonate-to-amide-I ratios. CFE also prevented the OVX-mediated decrease in mineral crystallinity. Nanoindentation parameters, including modulus and hardness, were decreased by OVX but CFE maintained these to the sham levels. Forskolin stimulated ALP, cAMP and cGMP in vitro and upregulated osteogenic genes in vivo.

Conclusion

CFE, likely due to the presence of forskolin displayed a bone-conserving effect via osteogenic and anti-resorptive mechanisms resulting in the maintenance of bone mass, microarchitecture, material, and strength.
The Gengnianchun recipe attenuates insulin resistance-induced diminished ovarian reserve through inhibiting the senescence of granulosa cells
Authors: Gao Hongna , Gao Lingyun , Rao Yanqiu , Qian Laidi , Li Mingqing , Wang Wenjun
Published: March 2023

Introduction

Insulin resistance (IR) is found in patients with polycystic ovary syndrome (PCOS), but the effects and mechanisms of IR on diminished ovarian reserve (DOR) remain unclear. This study set out to investigate the effects of IR on ovarian reserve; to explore the effects of high concentrations of insulin on the function of ovarian cells in vitro; and to validate the hypothesis that the Gengnianchun recipe (GNC) helps to attenuate DOR caused by IR through reducing the senescence of granulosa cells.

Methods

Estrus cycle, follicle count, and sex hormone levels were detected to evaluate ovarian function in mice with IR caused by feeding a high-fat diet (HFD). In addition, KGN cells (human granulosa cell line) were treated with high concentrations of insulin. The staining for senescence-associatedβ-galactosidase (SA-β-gal), cell cycle, and expression levels of mRNA and gene proteins related to cell aging were detected in KGN cells treated with high concentrations of insulin. Mice treated with an HFD were fed metformin, GNC, or saline solution for 6 weeks by oral gavage. HOMA-IR, the area under the curve (AUC) of the oral glucose tolerance test (OGTT), levels of fasting blood glucose (FBG), and fasting serum insulin (FINS) were examined to confirm the IR status. Then estrus cycle, follicle count, and sex hormone levels were detected to evaluate ovarian function. Expression levels of mRNA and gene proteins related to cell aging were detected in the ovarian tissue of mice in each group.

Results

The results demonstrated that IR reduced murine ovarian reserves, and high doses of insulin caused granulosa cells to senesce. There was a considerable improvement in HFD-induced IR status in the metformin (Met) and GNC treatment groups. In addition, the expression levels of aging-associated biomarkers were much lower in GNC mice than Met mice; and both the latter groups had considerably lower levels than the HFD group. Moreover, higher follicle counts in different stages and shorter diestrus in the Met or GNC groups compared to the HFD group indicated that ovarian aging could be largely reversed.

Discussion

This work showed that: IR impaired ovarian reserve; high concentrations of insulin induced granulosa cell aging; and GNC attenuated ovarian function through inhibiting IR-induced cell aging.
The Na+/K+-ATPase: A potential therapeutic target in cardiometabolic diseases
Authors: Obradovic Milan , Sudar-Milovanovic Emina , Gluvic Zoran , Banjac Katarina , Rizzo Manfredi , Isenovic Esma R.
Published: March 2023

Cardiometabolic diseases (CMD) are a direct consequence of modern living and contribute to the development of multisystem diseases such as cardiovascular diseases and diabetes mellitus (DM). CMD has reached epidemic proportions worldwide. A sodium pump (Na+/K+-ATPase) is found in most eukaryotic cells’ membrane and controls many essential cellular functions directly or indirectly. This ion transporter and its isoforms are important in the pathogenesis of some pathological processes, including CMD. The structure and function of Na+/K+-ATPase, its expression and distribution in tissues, and its interactions with known ligands such as cardiotonic steroids and other suspected endogenous regulators are discussed in this review. In addition, we reviewed recent literature data related to the involvement of Na+/K+-ATPase activity dysfunction in CMD, focusing on the Na+/K+-ATPase as a potential therapeutic target in CMD.
Adverse effect of assisted reproductive technology-related hyperoestrogensim on the secretion and absorption of uterine fluid in superovulating mice during the peri-implantation period
Authors: Xia Xinru , Zhang Yuan , Cao Meng , Yu Xiang , Gao Li , Qin Lianju , Wu Wei , Cui Yugui , Liu Jiayin
Published: March 2023

Objectives

This study aimed to investigate the potential mechanism of hyperoestrogensim elicited by ovulation induction affects endometrial receptivity and leads to embryo implantation abnormality or failure.

Study design

Establishment of ovulation induction mouse model. Changes in mouse body weight, ovarian weight, serum E2 level and oestrous cycle were observed. During the peri-implantation period, morphological changes in the mouse uterus and implantation sites and the localization and protein levels of oestrogen receptors ERα and ERβ, the tight junction factors CLDN3 and OCLN, the aquaporins AQP3, AQP4 and AQP8, and the sodium channel proteins SCNN1α, SCNN1β and SCNN1γ were observed. The expression and cellular localization of ERα, CLDN3, AQP8 and SCNN1 β in RL95-2 cell line were also detected by western blotting and immunofluorescence.

Results

Ovarian and body weights were significantly higher in the 5 IU and 10 IU groups than in the CON group. The E2 level was significantly higher in the 10 IU group than in the CON group. The mice in the 10 IU group had a disordered oestrous cycle and were in oestrus for a long time. At 5.5 dpc, significantly fewer implantation sites were observed in the 10 IU group than in the CON (p<0.001) and 5 IU (p<0.05) groups. The probability of abnormal implantation and abortion was higher in the 10 IU group than in the CON and 5 IU groups. CLDN3, OCLN, AQP8 and SCNN1β in the mouse endometrium were localized on the luminal epithelium and glandular epithelium and expression levels were lower in the 10 IU group than in the CON group. The protein expression level of ERα was increased by 50% in the 10 IU group compared to the CON group. The expressions of CLDN3, AQP8, SCNN1β in RL95-2 cell line were significantly depressed by the superphysiological E2, ERα agonist or ERβ agonist, which could be reversed by the oestrogen receptor antagonist.

Conclusion

ART-induced hyperoestrogenism reduces CLDN3, AQP8 and SCNN1β expression through ERα, thereby destroying tight junctions and water and sodium channels in the endometrial cavity epithelium, which may cause abnormal implantation due to abnormal uterine fluid secretion and absorption.
Progress and prospects of international carbon peaking and carbon neutral research –based on bibliometric analysis (1991–2022)
Authors: Zheng Ye , Li Zhenmiao , Chai Jinlai
Published: March 2023

Carbon peak and carbon neutrality is an important strategic measure to tackle climate change and is of great significance to global climate governance, human development, and scientific and technological progress. In this paper, we used 3,824 papers in the core collection of Web of Science from 1991 to 2022 as a sample, and used bibliometric analysis and CiteSpace, a visual knowledge network analysis tool, to sort out the current status of international carbon peak and carbon neutrality research in terms of publication trends, temporal distribution, spatial distribution, keyword co-occurrence mapping, and research basis. And then the current hot topics of research are explored,including carbon neutralization technology, climate policy impact and performance evaluation, carbon pricing and carbon finance, citizen participation attitude and behavior, and climate governance and global cooperation. Research prospects have been presented in terms of four aspects: building the integrated research framework of carbon peak and carbon neutral research, establishing a comprehensive and efficient environmental policy system, expanding research cooperation, deepening research and application of carbon peak carbon-neutral technology.
Group-living decrease predation risk of individual: Evidence from behavior, hormones and reproduction of plateau pika
Authors: Zhou Rui , Hua Rui , Tang Zhuangsheng , Hua Limin
Published: March 2023

Extensive research confirms that abiotic stressors like predation risk can profoundly affect animal condition. However, there is a lack of experimental research assessing the suite of physiological responses to risk. We increased predation risk in free-living plateau pikas (Ochotona curzoniae) by simulating natural chases using a model predator (UAV: unmanned aerial vehicle) and monitored behavior, physiology, and reproduction of pikas. We found that: Predation risk affects the body weight of plateau pika under different population density stress, but the effect is not significant. Compared with the non-predation risk treatment (control), the plateau pika under high population density stress mainly responded to the risk of predation by reducing the foraging time and increasing the vigilance time, while plateau pikas under low population density pressure not only reduce foraging time and appropriately increase vigilance time, but also focus on increasing the concealing time in the burrows. The corticosterone (CORT), cortisol and thyroid (T4) level of plateau pika with low population density under the predation risk was significantly higher than those in the control, and the testosterone (T), progesterone (PROG), leptin (LEP) and testicular weight of plateau pika with low population density in the predation risk was significantly lower than those in the control. There was no difference in the litter size of female pika between predation risk treatments and control. Broadly, our result show that predation risk had significant effects on the behavior, physiology and reproduction of plateau pikas with low population density, but had no significant effect with high population density, and the response of male plateau pika to predation risk was greater than that of female. Therefore, the prevention of plateau pika should focus on the control of population density and the protection of predators, so as to avoid the failure of ecological prevention methods such as natural enemies due to the increase of population density.
Single nucleotide variants in microRNA biosynthesis genes in Mexican individuals
Authors: Juárez-Luis Jesús , Canseco-Ocaña Moisés , Cid-Soto Miguel Angel , Castro-Martínez Xochitl H. , Martínez-Hernández Angélica , Orozco Lorena , Hernández-Zavala Araceli , Córdova Emilio J.
Published: March 2023

Background: MicroRNAs (miRNAs) are important regulators in a variety of biological processes, and their dysregulation is associated with multiple human diseases. Single nucleotide variants (SNVs) in genes involved in the processing of microRNAs may alter miRNA regulation and could present high allele heterogeneity in populations from different ethnic groups. Thus, the aim of this study was to genotype 15 SNVs in eight genes involved in the miRNA processing pathway in Mexican individuals and compare their frequencies across 21 populations from five continental groups.

Methods: Genomic DNA was obtained from 399 healthy Mexican individuals. SNVs in AGO2 (rs2293939 and rs4961280), DGCR8 (rs720012), DICER (rs3742330 and rs13078), DROSHA (rs10719 and rs6877842), GEMIN3 (rs197388 and rs197414), GEMIN4 (rs7813, rs2740349, and rs4968104), TNRC6B (rs9611280), and XP05 (rs11077 and rs34324334) were genotyped using TaqMan probes. The minor allele frequency of each SNV was compared to those reported in the 1,000 Genomes database using chi-squared. Sankey plot was created in the SankeyMATIC package to visualize the frequency range of each variant in the different countries analyzed.

Results: In Mexican individuals, all 15 SNVs were found in Hardy-Weinberg equilibrium, with frequencies ranging from 0.04 to 0.45. The SNVs rs4961280, rs2740349, rs34324334, and rs720012 in Mexican individuals had the highest minor allele frequencies worldwide, whereas the minor allele frequencies of rs197388, rs10719, rs197414, and rs1107 were among the lowest in Mexican individuals. The variants had high allele heterogeneity among the sub-continental populations, ranging from monomorphic, as was the case for rs9611280 and rs34324334 in African groups, to >0.50, which was the case for variants rs11077 and rs10719 in most of the populations. Importantly, the variants rs197388, rs720012, and rs197414 had FST values > 0.18, indicating a directional selective process. Finally, the SNVs rs13078 and rs10719 significantly correlated with both latitude and longitude.

Conclusion: These data indicate the presence of high allelic heterogeneity in the worldwide distribution of the frequency of SNVs located in components of the miRNA processing pathway, which could modify the genetic susceptibility associated with human diseases in populations with different ancestry.
Key genes associated with non-alcoholic fatty liver disease and hepatocellular carcinoma with metabolic risk factors
Authors: Yang Fan , Ni Beibei , Lian Qinghai , Qiu Xiusheng , He Yizhan , Zhang Qi , Zou Xiaoguang , He Fangping , Chen Wenjie
Published: March 2023

Background: Hepatocellular carcinoma (HCC) has become the world’s primary cause of cancer death. Obesity, hyperglycemia, and dyslipidemia are all illnesses that are part of the metabolic syndrome. In recent years, this risk factor has become increasingly recognized as a contributing factor to HCC. Around the world, non-alcoholic fatty liver disease (NAFLD) is on the rise, especially in western countries. In the past, the exact pathogenesis of NAFLD that progressed to metabolic risk factors (MFRs)-associated HCC has not been fully understood.

Methods: Two groups of the GEO dataset (including normal/NAFLD and HCC with MFRs) were used to analyze differential expression. Differentially expressed genes of HCC were verified by overlapping in TCGA. In addition, functional enrichment analysis, modular analysis, Receiver Operating Characteristic (ROC) analysis, LASSO analysis, and Genes with key survival characteristics were analyzed.

Results: We identified six hub genes (FABP5, SCD, CCL20, AGPAT9(GPAT3), PLIN1, and IL1RN) that may be closely related to NAFLD and HCC with MFRs. We constructed survival and prognosis gene markers based on FABP5, CCL20, AGPAT9(GPAT3), PLIN1, and IL1RN.This gene signature has shown good diagnostic accuracy in both NAFLD and HCC and in predicting HCC overall survival rates.

Conclusion: As a result of the findings of this study, there is some guiding significance for the diagnosis and treatment of liver disease associated with NAFLD progression.
Multi-omics analysis reveals focal adhesion characteristic associated tumor immune microenvironment in colon adenocarcinoma
Authors: Xu Xiaoming , Wang Jingzhi
Published: March 2023

Colon adenocarcinoma (COAD) is one of the most frequent malignant lesions of the digestive system in humans, with an insidious onset. At the time of diagnosis, most of them have developed to the middle and late stages, and cancer cells have metastasized, and the prognosis is poor. Treatment options for progressive COAD are limited, and despite the promise of immunotherapy, immunotherapy response rates are low. The assembly and disaggregation of focal adhesion are critical for the directional migration of tumor cells to different sites, and it is unclear whether focal adhesion-related genes are involved in the development and prognosis of colon adenocarcinoma. This study aimed to investigate the role of focal adhesion genes in the occurrence and prognosis of COAD. We obtained datasets of COAD patients, including RNA-sequencing data and clinical information, from the TCGA and GEO databases (GSE17538 and GSE39582). Through CNMF clustering, two molecular subtypes with different expression patterns of focal adhesion genes were identified, and it was found that the molecular subtype with low expression of focal adhesion genes had better prognosis. Then the prediction signature was constructed by LASSO-Cox regression model, and the receiver operating characteristic (ROC) curve showed that the 4-gene signature had a good prediction effect on COAD 1-, 2-, and 3-year OS. Gene function enrichment analysis showed that the high-risk group was mainly enriched in immune and adhesion-related signaling pathways, suggesting that focal adhesion genes may affect the development and prognosis of COAD by regulating the immune microenvironment and tumor metastasis. The interaction between focal adhesion genes and immunity during the occurrence of COAD may help improve the response rate of immunotherapy, which also provides new ideas for the molecular mechanism and targeted therapy in COAD.
Genome-wide association study to identify SNPs and candidate genes associated with body size traits in donkeys
Authors: Song Shuang , Wang Shiwei , Li Nan , Chang Siyu , Dai Shizhen , Guo Yajun , Wu Xuan , Cheng Yuanweilu , Zeng Shenming
Published: March 2023

The Yangyuan donkey is a domestic animal breed mainly distributed in the northwest region of Hebei Province. Donkey body shape is the most direct production index, can fully reflect the donkey’s growth status, and is closely related to important economic traits. As one of the main breeding selection criteria, body size traits have been widely used to monitor animal growth and evaluate the selection response. Molecular markers genetically linked to body size traits have the potential to accelerate the breeding process of animals via marker-assisted selection. However, the molecular markers of body size in Yangyuan donkeys have yet to be explored. In this study, we performed a genome-wide association study to identify the genomic variations associated with body size traits in a population of 120 Yangyuan donkeys. We screened 16 single nucleotide polymorphisms that were significantly associated with body size traits. Some genes distributed around these significant SNPs were considered candidates for body size traits, including SMPD4, RPS6KA6, LPAR4, GLP2R, BRWD3, MAGT1, ZDHHC15, and CYSLTR1. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses indicated that these genes were mainly involved in the P13K-Akt signaling pathway, Rap1 signaling pathway, regulation of actin cytoskeleton, calcium signaling pathway, phospholipase D signaling pathway, and neuroactive ligand-receptor interactions. Collectively, our study reported on a list of novel markers and candidate genes associated with body size traits in donkeys, providing useful information for functional gene studies and offering great potential for accelerating Yangyuan donkey breeding.
Comparison of mifepristone plus misoprostol with misoprostol alone for first trimester medical abortion: A systematic review and meta-analysis
Authors: Shimels Tariku , Getnet Melsew , Shafie Mensur , Belay Lemi
Published: March 2023

Objective

To compare mifepristone plus a misoprostol-combined regimen with misoprostol alone in the medical abortion of first trimester pregnancy.

Methods

An internet-based search of available literature was performed using text words contained in titles and abstracts. PubMed/Medline, Cochrane CENTRAL, EMBASE, and Google scholar were used to locate English-based articles published until December 2021. Studies fulfilling the inclusion criteria were selected, appraised, and assessed for methodological quality. The included studies were pooled for meta-analysis, and the results were presented in risk ratio at a 95% confidence interval.

Findings

Nine studies comprising 2,052 participants (1,035 intervention and 1,017 controls) were considered. Primary endpoints were complete expulsion, incomplete expulsion, missed abortion, and ongoing pregnancy. The intervention was found to more likely induce complete expulsion irrespective of gestational age (RR: 1.19; 95% CI: 1.14–1.25). The administration of misoprostol 800 mcg after 24 h of mifepristone pre-treatment in the intervention group more likely induced complete expulsion (RR: 1.23; 95% CI: 1.17–1.30) than after 48 h. The intervention group was also more likely to experience complete expulsion when misoprostol was used either vaginally (RR: 1.16; 95% CI: 1.09–1.17) or buccally (RR: 1.23; 95% CI: 1.16–1.30). The intervention was more effective in the subgroup with a negative foetal heartbeat at reducing incomplete abortion (RR: 0.45; 95% CI: 0.26–0.78) compared with the control group. The intervention more likely reduced both missed abortion (RR: 0.21; 95% CI: 0.08–0.91) and ongoing pregnancy (RR: 0.12; 95% CI: 0.05–0.26). Fever was less likely to be reported (RR: 0.78; 95% CI: 0.12–0.89), whereas the subjective experience of bleeding was more likely to be encountered (RR: 1.31; 95% CI: 1.13–1.53) by the intervention group.

Conclusion

The review strengthened the theory that a combined mifepristone and misoprostol regimen can be an effective medical management for inducing abortions during first trimester pregnancy in all contexts. Specifically, there is a high-level certainty of evidence on complete expulsion during the early stage and its ability to reduce both missed and ongoing pregnancies.

Systematic Review Registration

https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42019134213, identifier CRD42019134213.
Changes of tumor microenvironment in non-small cell lung cancer after TKI treatments
Authors: Chen Shanshan , Tang Jingyi , Liu Fen , Li Wei , Yan Ting , Shangguan Dangang , Yang Nong , Liao Dehua
Published: March 2023

Non-small cell lung cancer (NSCLC) is the most common lung cancer diagnosis, among which epidermal growth factor receptor (EGFR), Kirsten rat sarcoma (KRAS), and anaplastic lymphoma kinase (ALK) mutations are the common genetic drivers. Their relative tyrosine kinase inhibitors (TKIs) have shown a better response for oncogene-driven NSCLC than chemotherapy. However, the development of resistance is inevitable following the treatments, which need a new strategy urgently. Although immunotherapy, a hot topic for cancer therapy, has shown an excellent response for other cancers, few responses for oncogene-driven NSCLC have been presented from the existing evidence, including clinical studies. Recently, the tumor microenvironment (TME) is increasingly thought to be a key parameter for the efficacy of cancer treatment such as targeted therapy or immunotherapy, while evidence has also shown that the TME could be affected by multi-factors, such as TKIs. Here, we discuss changes in the TME in NSCLC after TKI treatments, especially for EGFR-TKIs, to offer information for a new therapy of oncogene-driven NSCLC.
Immunogenicity against wild-type and Omicron SARS-CoV-2 after a third dose of inactivated COVID-19 vaccine in healthy adolescents
Authors: Leung Daniel , Cohen Carolyn A. , Mu Xiaofeng , Rosa Duque Jaime S. , Cheng Samuel M. S. , Wang Xiwei , Wang Manni , Zhang Wenyue , Zhang Yanmei , Tam Issan Y. S. , Lam Jennifer H. Y. , Chan Sau Man , Chaothai Sara , Kwan Kelvin K. H. , Chan Karl C. K. , Li John K. C. , Luk Leo L. H. , Tsang Leo C. H. , Chu Nym Coco , Wong Wilfred H. S. , Mori Masashi , Leung Wing Hang , Valkenburg Sophie , Peiris Malik , Tu Wenwei , Lau Yu Lung
Published: March 2023

Introduction

Two doses of inactivated SARS-CoV-2 vaccine CoronaVac cannot elicit high efficacy against symptomatic COVID-19, especially against the Omicron variant, but that can be improved by a third dose in adults. The use of a third dose of CoronaVac in adolescents may be supported by immunobridging studies in the absence of efficacy data.

Methods

With an immunobridging design, our study (NCT04800133) tested the non-inferiority of the binding and neutralizing antibodies and T cell responses induced by a third dose of CoronaVac in healthy adolescents (N=94, median age 14.2 years, 56% male) compared to adults (N=153, median age 48.1 years, 44% male). Responses against wild-type (WT) and BA.1 SARS-CoV-2 were compared in adolescents. Safety and reactogenicity were also monitored.

Results

A homologous third dose of CoronaVac further enhanced antibody response in adolescents compared to just 2 doses. Adolescents mounted non-inferior antibody and T cell responses compared to adults. Although S IgG and neutralizing antibody responses to BA.1 were lower than to WT, they remained detectable in 96% and 86% of adolescents. T cell responses to peptide pools spanning only the mutations of BA.1 S, N and M in adolescents were preserved, increased, and halved compared to WT respectively. No safety concerns were identified.

Discussion

The primary vaccination series of inactivated SARS-CoV-2 vaccines for adolescents should include 3 doses for improved humoral immunogenicity.
Quantitative and causal analysis for inflammatory genes and the risk of Parkinson’s disease
Authors: Yi Minhan , Li Jiaxin , Jian Shijie , Li Binbin , Huang Zini , Shu Li , Zhang Yuan
Published: March 2023

Background

The dysfunction of immune system and inflammation contribute to the Parkinson’s disease (PD) pathogenesis. Cytokines, oxidative stress, neurotoxin and metabolism associated enzymes participate in neuroinflammation in PD and the genes involved in them have been reported to be associated with the risk of PD. In our study, we performed a quantitative and causal analysis of the relationship between inflammatory genes and PD risk.

Methods

Standard process was performed for quantitative analysis. Allele model (AM) was used as primary outcome analysis and dominant model (DM) and recessive model (RM) were applied to do the secondary analysis. Then, for those genes significantly associated with the risk of PD, we used the published GWAS summary statistics for Mendelian Randomization (MR) to test the causal analysis between them.

Results

We included 36 variants in 18 genes for final pooled analysis. As a result, IL-6 rs1800795, TNF-α rs1799964, PON1 rs854560, CYP2D6 rs3892097, HLA-DRB rs660895, BST1 rs11931532, CCDC62 rs12817488 polymorphisms were associated with the risk of PD statistically with the ORs ranged from 0.66 to 3.19 while variants in IL-1α, IL-1β, IL-10, MnSOD, NFE2L2, CYP2E1, NOS1, NAT2, ABCB1, HFE and MTHFR were not related to the risk of PD. Besides, we observed that increasing ADP-ribosyl cyclase (coded by BST1) had causal effect on higher PD risk (OR[95%CI] =1.16[1.10-1.22]) while PON1(coded by PON1) shown probably protective effect on PD risk (OR[95%CI] =0.81[0.66-0.99]).

Conclusion

Several polymorphisms from inflammatory genes of IL-6, TNF-α, PON1, CYP2D6, HLA-DRB, BST1, CCDC62 were statistically associated with the susceptibility of PD, and with evidence of causal relationships for ADP-ribosyl cyclase and PON1 on PD risk, which may help understand the mechanisms and pathways underlying PD pathogenesis.
Neoadjuvant immunotherapy for colorectal cancer: Right regimens, right patients, right directions?
Authors: Zhu Jiahao , Lian Jie , Xu Benjie , Pang Xiangyi , Ji Shengjun , Zhao Yutian , Lu Haibo
Published: March 2023

Neoadjuvant chemoradiotherapy (NACRT) or chemotherapy (NACT) followed by radical resection and then adjuvant therapy is considered the optimal treatment model for locally advanced colorectal cancer (LACRC). A recent total neoadjuvant therapy (TNT) strategy further improved the tumour regression rate preoperatively and reduced local-regional recurrence in locally advanced rectal cancer (LARC). However, distant metastasis was still high, and little overall survival benefit was obtained from these preoperative treatment models. According to mismatch repair protein expression, MSI-H/dMMR and non-MSI-H/pMMR statuses were defined in colorectal cancer (CRC) patients. Due to the special features of biologics in MSI-H/dMMR CRC patients, this subgroup of patients achieved little treatment efficacy from chemoradiotherapy but benefited from immune checkpoint inhibitors (ICIs). The KEYNOTE-177 trial observed favourable survival outcomes in metastatic CRC patients treated with one-line pembrolizumab with tolerable toxicity. Given the better systemic immune function, increased antigenic exposure, and improved long-term memory induction before surgery, neoadjuvant ICI (NAICI) treatment was proposed. The NICHE trial pioneered the use of NAICI treatment in LACRC, and recent reports from several phase II studies demonstrated satisfactory tumour downsizing in CRC. Preclinical rationales and preliminary early-phase human trials reveal the feasibility of NAICI therapy and the therapeutic efficacy provided by this treatment model. Better tumour regression before surgery also increases the possibility of organ preservation for low LARC. However, the optimal treatment strategy and effective biomarker identification for beneficiary selection remain unknown, and potential pitfalls exist, including tumour progression during neoadjuvant treatment due to drug resistance and surgery delay. Given these foundations and questions, further phase II or III trials with large samples need to be conducted to explore the right regimens for the right patients.
Long-term adaptive response in COVID-19 vaccine recipients and the effect of a booster dose
Authors: Perico Luca , Todeschini Marta , Casiraghi Federica , Mister Marilena , Pezzotta Anna , Peracchi Tobia , Tomasoni Susanna , Trionfini Piera , Benigni Ariela , Remuzzi Giuseppe
Published: March 2023

We examined the immune response in subjects previously infected with SARS-CoV2 and infection-naïve 9 months after primary 2-dose COVID-19 mRNA vaccination and 3 months after the booster dose in a longitudinal cohort of healthcare workers. Nine months after primary vaccination, previously infected subjects exhibited higher residual antibody levels, with significant neutralizing activity against distinct variants compared to infection-naïve subjects. The higher humoral response was associated with higher levels of receptor binding domain (RBD)-specific IgG+ and IgA+ memory B cells. The booster dose increased neither neutralizing activity, nor the B and T cell frequencies. Conversely, infection-naïve subjects needed the booster to achieve comparable levels of neutralizing antibodies as those found in previously infected subjects after primary vaccination. The neutralizing titer correlated with anti-RBD IFNγ producing T cells, in the face of sustained B cell response. Notably, pre-pandemic samples showed high Omicron cross-reactivity. These data show the importance of the booster dose in reinforcing immunological memory and increasing circulating antibodies in infection-naïve subjects.
Transmission of Zika virus by dendritic cell subsets in skin and vaginal mucosa
Authors: Eder Julia , Zijlstra-Willems Esther , Koen Gerrit , Kootstra Neeltje A. , Wolthers Katja C. , Geijtenbeek Teunis B.
Published: March 2023

Zika virus is a member of the Flaviviridae family that has caused recent outbreaks associated with neurological malformations. Transmission of Zika virus occurs primarily via mosquito bite but also via sexual contact. Dendritic cells (DCs) and Langerhans cells (LCs) are important antigen presenting cells in skin and vaginal mucosa and paramount to induce antiviral immunity. To date, little is known about the first cells targeted by Zika virus in these tissues as well as subsequent dissemination of the virus to other target cells. We therefore investigated the role of DCs and LCs in Zika virus infection. Human monocyte derived DCs (moDCs) were isolated from blood and primary immature LCs were obtained from human skin and vaginal explants. Zika virus exposure to moDCs but not skin and vaginal LCs induced Type I Interferon responses. Zika virus efficiently infected moDCs but neither epidermal nor vaginal LCs became infected. Infection of a human full skin model showed that DC-SIGN expressing dermal DCs are preferentially infected over langerin+ LCs. Notably, not only moDCs but also skin and vaginal LCs efficiently transmitted Zika virus to target cells. Transmission by LCs was independent of direct infection of LCs. These data suggest that DCs and LCs are among the first target cells for Zika virus not only in the skin but also the genital tract. The role of vaginal LCs in dissemination of Zika virus from the vaginal mucosa further emphasizes the threat of sexual transmission and supports the investigation of prophylaxes that go beyond mosquito control.