bluuebunny/crossref_metadata_2025 huggingface dataset:
Novel Corneal Protein Biomarker Candidates Reveal Iron Metabolic Disturbance in High Myopia Eyes
Authors: Chen Jingyi , Wu Wenjing , Wang Zhiqian , Zhai Chuannan , Deng Baocheng , Alzogool Mohammad , Wang Yan
Published: October 2021

Myopia is a major public health concern with increasing global prevalence and is the leading cause of vision loss and complications. The potential role of the cornea, a substantial component of refractive power and the protective fortress of the eye, has been underestimated in the development of myopia. Our study acquired corneal stroma tissues from myopic patients undergoing femtosecond laser-assisted small incision lenticule extraction (SMILE) surgery and investigated the differential expression of circulating proteins between subjects with low and high myopia by means of high-throughput proteomic approaches—the quantitative tandem mass tag (TMT) labeling method and parallel reaction monitoring (PRM) validation. Across all corneal stroma tissue samples, a total of 2,455 proteins were identified qualitatively and quantitatively, 103 of which were differentially expressed between those with low and high myopia. The differentially abundant proteins (DAPs) between the groups of stroma samples mostly demonstrated catalytic activity and molecular function regulator and transporter activity and participated in metabolic processes, biological regulation, response to stimulus, and so forth. Pathway enrichment showed that mineral absorption, ferroptosis, and HIF-1 signaling pathways were activated in the human myopic cornea. Furthermore, TMT analysis and PRM validation revealed that the expression of ferritin light chain (FTL, P02792) and ferritin heavy chain (FTH1, P02794) was negatively associated with myopia development, while the expression of serotransferrin (TF, P02787) was positively related to myopia status. Overall, our results indicated that subjects with low and high myopia could have different proteomic profiles or signatures in the cornea. These findings revealed disturbances in iron metabolism and corneal oxidative stress in the more myopic eyes. Iron metabolic proteins could serve as an essential modulator in the pathogenesis of myopia.
Mutated VWA8 Is Associated With Developmental Delay, Microcephaly, and Scoliosis and Plays a Novel Role in Early Development and Skeletal Morphogenesis in Zebrafish
Authors: Umair Muhammad , Farooq Khan Muhammad , Aldrees Mohammed , Nashabat Marwan , Alhamoudi Kheloud M. , Bilal Muhammad , Alyafee Yusra , Al Tuwaijri Abeer , Aldarwish Manar , Al-Rumayyan Ahmed , Alkhalaf Hamad , Wadaan Mohammad A. M. , Alfadhel Majid
Published: October 2021

Von Willebrand A domain-containing protein 8 (VWA8), also named KIAA0564, is a poorly characterized, mitochondrial matrix-targeted protein having a putative ATPase activity. VWA8 is comprising of ATPase-associated domains and a VWFA domain associated with ATPase activity inside the cell. In the present study, we describe a large consanguineous family of Saudi origin segregating a complex developmental syndrome in an autosomal recessive fashion. All the affected individuals exhibited severe developmental disorders. DNA from three patients was subjected to whole-exome sequencing followed by Sanger sequencing. VWA8 knock-down zebrafish morpholinos were used to study the phenotypic effect of this gene on zebrafish development. A homozygous missense variant [c.947A > G; p.(Asp316Gly)] was identified in exon 8 of the VWA8 gene, which perfectly segregated with the disease phenotype. Using zebrafish morpholino, we observed delayed development at an early stage, lack of movement, light sensitivity, severe skeletal deformity such as scoliosis, and facial dysmorphism. This is the first homozygous variant identified in the VWA8 gene underlying global developmental delay, microcephaly, scoliosis, limbs, and cardiovascular malformations in humans. We provide genetic and molecular evidence using zebrafish morpholino for a homozygous variant in the VWA8 gene, associated with such a complex developmental syndrome in humans.
Dynamic m6A mRNA Methylation Reveals the Role of METTL3/14-m6A-MNK2-ERK Signaling Axis in Skeletal Muscle Differentiation and Regeneration
Authors: Xie Shu-Juan , Lei Hang , Yang Bing , Diao Li-Ting , Liao Jian-You , He Jie-Hua , Tao Shuang , Hu Yan-Xia , Hou Ya-Rui , Sun Yu-Jia , Peng Yan-Wen , Zhang Qi , Xiao Zhen-Dong
Published: October 2021

N6-methyladenosine (m6A) RNA methylation has emerged as an important factor in various biological processes by regulating gene expression. However, the dynamic profile, function and underlying molecular mechanism of m6A modification during skeletal myogenesis remain elusive. Here, we report that members of the m6A core methyltransferase complex, METTL3 and METTL14, are downregulated during skeletal muscle development. Overexpression of either METTL3 or METTL14 dramatically blocks myotubes formation. Correspondingly, knockdown of METTL3 or METTL14 accelerates the differentiation of skeletal muscle cells. Genome-wide transcriptome analysis suggests ERK/MAPK is the downstream signaling pathway that is regulated to the greatest extent by METTL3/METTL14. Indeed, METTL3/METTL14 expression facilitates ERK/MAPK signaling. Via MeRIP-seq, we found that MNK2, a critical regulator of ERK/MAPK signaling, is m6A modified and is a direct target of METTL3/METTL14. We further revealed that YTHDF1 is a potential reader of m6A on MNK2, regulating MNK2 protein levels without affecting mRNA levels. Furthermore, we discovered that METTL3/14-MNK2 axis was up-regulated notably after acute skeletal muscle injury. Collectively, our studies revealed that the m6A writers METTL3/METTL14 and the m6A reader YTHDF1 orchestrate MNK2 expression posttranscriptionally and thus control ERK signaling, which is required for the maintenance of muscle myogenesis and may contribute to regeneration.
Challenges for the Applications of Human Pluripotent Stem Cell-Derived Liver Organoids
Authors: Chang Mingyang , Bogacheva Mariia S. , Lou Yan-Ru
Published: October 2021

The current organoid culture systems allow pluripotent and adult stem cells to self-organize to form three-dimensional (3D) structures that provide a faithful recapitulation of the architecture and function of in vivo organs. In particular, human pluripotent stem cell-derived liver organoids (PSC-LOs) can be used in regenerative medicine and preclinical applications, such as disease modeling and drug discovery. New bioengineering tools, such as microfluidics, biomaterial scaffolds, and 3D bioprinting, are combined with organoid technologies to increase the efficiency of hepatic differentiation and enhance the functional maturity of human PSC-LOs by precise control of cellular microenvironment. Long-term stabilization of hepatocellular functions of in vitro liver organoids requires the combination of hepatic endodermal, endothelial, and mesenchymal cells. To improve the biological function and scalability of human PSC-LOs, bioengineering methods have been used to identify diverse and zonal hepatocyte populations in liver organoids for capturing heterogeneous pathologies. Therefore, constructing engineered liver organoids generated from human PSCs will be an extremely versatile tool in in vitro disease models and regenerative medicine in future. In this review, we aim to discuss the recent advances in bioengineering technologies in liver organoid culture systems that provide a timely and necessary study to model disease pathology and support drug discovery in vitro and to generate cell therapy products for transplantation.
A Novel Three-Dimensional Culture Device Favors a Myelinating Morphology of Neural Stem Cell-Derived Oligodendrocytes
Authors: Flagelli Alessandra , Candini Olivia , Frabetti Stella , Dominici Massimo , Giardino Luciana , Calzà Laura , Baldassarro Vito Antonio
Published: October 2021

The complexity of the central nervous system (CNS) requires researchers to consider all the variables linked to the interaction between the different cell inhabitants. On this basis, any in vitro study of the physiological and pathological processes regarding the CNS should consider the balance between the standardization of the assay and the complexity of the cellular system which mimics the in vivo microenvironment. One of the main structural and functional components of the CNS is the oligodendrocyte precursor cell (OPC), responsible for developmental myelination and myelin turnover and repair during adulthood following differentiation into mature oligodendrocytes. In the present brief research report, we describe a 3D culture tool (VITVO) based on an inert and biocompatible synthetic polymer material scaffold, functionalized with laminin coating, and tested as a new culture microenvironment for neural stem/precursor cell (NSPC) differentiation compared to standard 2D cultures. NSPCs spontaneously differentiate in the three neural lineages (neurons, astrocytes and OPCs), identified by specific markers, along the fibers in the 3D structure. Analysis of the mRNA levels for lineage differentiation markers reveals a higher expression compared to those seeded on a 2D surface, suggesting an acceleration of the differentiation process. We then focused on the oligodendroglial lineage, showing that in VITVO, mature oligodendrocytes exhibit a myelinating morphology, proven by 3D image elaboration, linked to a higher expression of mature oligodendrocyte markers. This preliminary study on an innovative 3D culture system is the first robust step in producing new microenvironment-based strategies to investigate in vitro OPC and oligodendrocyte biology.
Murine Susceptibility to Leishmania amazonensis Infection Is Influenced by Arginase-1 and Macrophages at the Lesion Site
Authors: Tomiotto-Pellissier Fernanda , Miranda-Sapla Milena Menegazzo , Silva Taylon Felipe , Bortoleti Bruna Taciane da Silva , Gonçalves Manoela Daiele , Concato Virginia Márcia , Rodrigues Ana Carolina Jacob , Detoni Mariana Barbosa , Staurengo-Ferrari Larissa , Verri Waldiceu Aparecido , Costa Idessania Nazareth , Panis Carolina , Conchon-Costa Ivete , Bordignon Juliano , Pavanelli Wander Rogério
Published: October 2021

Cutaneous leishmaniasis is a zoonotic infectious disease broadly distributed worldwide, causing a range of diseases with clinical outcomes ranging from self-healing infections to chronic disfiguring disease. The effective immune response to this infection is yet to be more comprehensively understood and is fundamental for developing drugs and vaccines. Thus, we used experimental models of susceptibility (BALB/c) and partial resistance (C57BL/6) toLeishmania amazonensisinfection to investigate the local profile of mediators involved in the development of cutaneous leishmaniasis. We found worse disease outcome in BALB/c mice than in C57BL/6 mice, with almost 15 times higher parasitic load, ulcerated lesion formation, and higher levels of IL-6 in infected paws. In contrast, C57BL/6 presented higher levels of IFN-γ and superoxide anion(•O2−)after 11 weeks of infection and no lesion ulcerations. A peak of local macrophages appeared after 24 h of infection in both of the studied mice strains, followed by another increase after 240 h, detected only in C57BL/6 mice. Regarding M1 and M2 macrophage phenotype markers [iNOS, MHC-II, CD206, and arginase-1 (Arg-1)], we found a pronounced increase in Arg-1 levels in BALB/c after 11 weeks of infection, whereas C57BL/6 showed an initial predomination of markers from both profiles, followed by an M2 predominance, coinciding with the second peak of macrophage infiltration, 240 h after the infection. Greater deposition of type III collagen and lesion resolution was also observed in C57BL/6 mice. The adoptive transfer of macrophages from C57BL/6 to infected BALB/c at the 11th week showed a reduction in both edema and the number of parasites at the lesion site, in addition to lower levels of Arg-1. Thus, C57BL/6 mice have a more effective response againstL. amazonensis, based on a balance between inflammation and tissue repair, while BALB/c mice have an excessive Arg-1 production at late infection. The worst evolution seems to be influenced by recruitment of Arg-1 related macrophages, since the adoptive transfer of macrophages from C57BL/6 mice to BALB/c resulted in better outcomes, with lower levels of Arg-1.
Chronic Urinary Infection in Overactive Bladder Syndrome: A Prospective, Blinded Case Control Study
Authors: Khan Zainab , Healey Gareth D. , Paravati Roberta , Berry Nidhika , Rees Eugene , Margarit Lavinia , Gonzalez Deyarina , Emery Simon , Conlan Robert Steven
Published: October 2021

Objectives

To investigate whether women with overactive bladder (OAB) symptoms and no evidence of clinical infection by conventional clean-catch midstream urine cultures have alternative indicators of sub-clinical infection.

Patients/Subjects, Materials & Methods

The study was a prospective, blinded case-control study with 147 participants recruited, including 73 OAB patients and 74 controls. The OAB group comprised female patients of at least 18 years of age who presented with OAB symptoms for more than 3 months. Clean-catch midstream urine samples were examined for pyuria by microscopy; subjected to routine and enhanced microbiological cultures and examined for the presence of 10 different cytokines, chemokines, and prostaglandins by ELISA.

Results

The mean age and BMI of participants in both groups were similar. No significant difference in the number of women with pyuria was observed between OAB and control groups (p = 0.651). Routine laboratory cultures were positive in three (4%) of women in the OAB group, whereas the enhanced cultures isolated bacteria in 17 (23.2%) of the OAB patients. In the control group, no positive cultures were observed using routine laboratory cultures, whereas enhanced culture isolated bacteria in 8 (10.8%) patients. No significant differences were observed in the concentrations of PGE2, PGF2α, MCP-1, sCD40L, MIP-1β, IL12p70/p40, IL12/IL-23p40, IL-5, EGF and GRO-α between the OAB and control groups.

Conclusions

Patients with OAB symptoms have significant bacterial growth on enhanced culture of the urine, which is often not detectable through routine culture, suggesting a subclinical infection. Enhanced culture techniques should therefore be used routinely for the effective diagnosis and management of OAB.
Quantitative Analysis of Myocardial Work by Non-invasive Left Ventricular Pressure-Strain Loop in Patients With Type 2 Diabetes Mellitus
Authors: Huang Danqing , Cui Cunying , Zheng Qiang , Li Yanan , Liu Yuanyuan , Hu Yanbin , Wang Ying , Liu Ruijie , Liu Lin
Published: October 2021

Background: Type 2 diabetes mellitus (T2DM) is a common risk factor for cardiovascular diseases. The aims of this study were to evaluate the changes in the left ventricular myocardial work in T2DM patients using the left ventricular pressure-strain loop (PSL) technique, and to explore the risk factors for the left ventricular myocardial work impairment.

Methods: Fifty patients with T2DM and 50 normal controls (NCs) were included in the study. In addition to conventional echocardiography and two-dimensional speckle tracking echocardiography, the left ventricular myocardial work parameters were measured using PSL technology.

Results: The absolute value for global longitudinal strain (GLS), global work index (GWI) and, global constructive work (GCW) were significantly decreased in the T2DM group (P < 0.05), while the left ventricular ejection fraction (LVEF) was not significantly different between the T2DM and NC groups. Multivariable linear regression analysis showed that hemoglobin A1c (HbA1c) was independently related to GWI (β = −0.452, P < 0.05), while HbA1c and the diabetes duration were independently related to GCW (β = −0.393, P < 0.05 and β = −0.298, P < 0.05, respectively).

Conclusions: Changes in the left ventricular myocardial systolic function in T2DM patients were identified using PSL technology. HbA1c was shown to be an independent risk factor affecting GWI, while HbA1c and diabetes duration were demonstrated to be independent risk factors affecting GCW.
Recent Insight on the Non-coding RNAs in Mesenchymal Stem Cell-Derived Exosomes: Regulatory and Therapeutic Role in Regenerative Medicine and Tissue Engineering
Authors: Pant Tarun , Juric Matea , Bosnjak Zeljko J. , Dhanasekaran Anuradha
Published: October 2021

Advances in the field of regenerative medicine and tissue engineering over the past few decades have paved the path for cell-free therapy. Numerous stem cell types, including mesenchymal stem cells (MSCs), have been reported to impart therapeutic effects via paracrine secretion of exosomes. The underlying factors and the associated mechanisms contributing to these MSC-derived exosomes' protective effects are, however, poorly understood, limiting their application in the clinic. The exosomes exhibit a diversified repertoire of functional non-coding RNAs (ncRNAs) and have the potential to transfer these biologically active transcripts to the recipient cells, where they are found to modulate a diverse array of functions. Altered expression of the ncRNAs in the exosomes has been linked with the regenerative potential and development of various diseases, including cardiac, neurological, skeletal, and cancer. Also, modulating the expression of ncRNAs in these exosomes has been found to improve their therapeutic impact. Moreover, many of these ncRNAs are expressed explicitly in the MSC-derived exosomes, making them ideal candidates for regenerative medicine, including tissue engineering research. In this review, we detail the recent advances in regenerative medicine and summarize the evidence supporting the altered expression of the ncRNA repertoire specific to MSCs under different degenerative diseases. We also discuss the therapeutic role of these ncRNA for the prevention of these various degenerative diseases and their future in translational medicine.
Role of PCSK9 in Homocysteine-Accelerated Lipid Accumulation in Macrophages and Atherosclerosis in ApoE−/− Mice
Authors: Jin Ping , Gao Dengfeng , Cong Guangzhi , Yan Ru , Jia Shaobin
Published: October 2021

Background: Homocysteine (Hcy) has been established as an independent risk factor for atherosclerosis, and the involvement of hyperhomocysteinemia (HHcy) in atherosclerotic lesions is complex. Proprotein convertase subtilisin kexin 9 (PCSK9) has vital importance in lipid metabolism, and its inhibitors have intense lipid-lowering and anti-atherosclerotic effects. However, the underlying effect of PCSK9 on HHcy-accelerated dyslipidemia of macrophages is still uncertain. The purpose of this study was to investigate the potential role of PCSK9 in Hcy-induced lipid accumulation and atherosclerotic lesions.

Methods:In vitro, gene and protein expressions were assessed by real-time quantitative PCR and western blot in THP-1 macrophages with Hcy incubation. Lipid accumulation and cholesterol efflux were evaluated with Hcy treatment. SBC-115076 was used to examine the role of PCSK9 in ATP-binding cassette transporter A1 and G1 (ABCA1 and ABCG1)-dependent cholesterol efflux. In vivo, lesion area, lipid deposition and collagen contents were determined in aortas of ApoE−/− mice under a methionine diet. SBC-115076 was subcutaneously injected to explore the potential effects of PCSK9 inhibition on alleviating the severity of HHcy-related atherosclerotic lesions.

Results: In THP-1 macrophages, Hcy dose- and time-dependently promoted PCSK9 gene and protein levels without regulating the translation of Low-density lipoprotein receptor (LDLR). SBC-115076 used to inhibit PCSK9 largely alleviated lipid accumulation and reversed the cholesterol efflux to apolipoprotein-I(apoA-I) and high-density lipoprotein (HDL) mediated by ABCA1 and ABCG1. In ApoE−/− mice, methionine diet induced HHcy caused larger lesion area and more lipid accumulation in aortic roots. SBC-115076 reduced atherosclerotic severity by reducing the lesion area and lipid accumulation and increasing expressions of ABCA1 and ABCG1 in macrophages from atherosclerotic plaque. In addition, SBC-115076 decreased plasma Hcy level and lipid profiles significantly.

Conclusion: PCSK9 promoted lipid accumulation via inhibiting cholesterol efflux mediated by ABCA1 and ABCG1 from macrophages and accelerated atherosclerotic lesions under HHcy treatment. Inhibiting PCSK9 may have anti-atherogenic properties in HHcy-accelerated atherosclerosis.
Identifying Land Degradation and its Driving Factors in the Aral Sea Basin From 1982 to 2015
Authors: Berdimbetov Timur , Ma Zhu-Guo , Shelton Sherly , Ilyas Sana , Nietullaeva Sahibjamal
Published: October 2021

Land degradation is one of the critical ecological issue in the Aral Sea Basin (ASB). This study investigates land degradation in ASB during 1982–2015 using the Normalized Difference Vegetation Index (NDVI) as a proxy. The residual trend (RESTREND) for temperature, precipitation, soil moisture adjusted NDVI has been applied to identify the land degradation in ASB and quantify the contribution of climate factors such as temperature and rainfall. In addition, a binary logistic regression model is adopted to assess the contributions of land transition, socio-economic, and topographical conditions on land degradation. Based on RESTREND, the relative contribution of precipitation (30.2%), soil moisture (23%), and temperature (11.4%) indicates that precipitation is one of the main driving factors of land degradation. The results further revealed that 36.5% of ASB is degraded, which is mostly concentrated in the lower part of the ASB. In contrast, 33.2% of ASB depicts land improvement, especially in the upper part of the basin. According to the land transition assessment, 66.6% of the water area and 11.68% of forest converted to barren land and shrubland during the study period, respectively. The binary logistic regression model demonstrated water and forest area transitions into shrubland and barren land as the major contributors of contemporary land degradation in ASB. Cropland recorded a net increment by 2.69% of its initial area, and the abandoned cropland converted to shrubland and barren lands that negatively impacted land cover change. This in-depth analysis of land degradation can assist in designing pragmatic policy interventions for implementing land restoration plans in the area.
Inclusive Instructional Practices: Course Design, Implementation, and Discourse
Authors: Salehi Shima , Ballen Cissy J. , Trujillo Gloriana , Wieman Carl
Published: October 2021

As national efforts strive to make STEM more inclusive, it is important to identify instructional practices that maximize effective learning for all and provide students from different demographic and educational backgrounds equal opportunities to excel. Here, we present a guideline for inclusive instructional practices based on findings from 1) cognitive psychology about learning and memory, 2) social psychology about creating inclusive discourse, and 3) discipline-based education research (DBER) about effective learning practices in STEM higher education. Our aim is to promote equity across STEM education by providing researchers and instructors across different STEM fields with concrete suggestions for implementing inclusive instructional practices in their courses.
BMSC-Derived Exosomes Inhibit Dexamethasone-Induced Muscle Atrophy via the miR-486-5p/FoxO1 Axis
Authors: Li Ziyi , Liu Chang , Li Shilun , Li Ting , Li Yukun , Wang Na , Bao Xiaoxue , Xue Peng , Liu Sijing
Published: October 2021

Sarcopenia, characterized by reduced muscle function as well as muscle mass, has been a public health problem with increasing prevalence. It might result from aging, injury, hormone imbalance and other catabolic conditions. Recently, exosomes were considered to regulate muscle regeneration and protein synthesis. In order to confirm the effect of BMSC-derived exosomes (BMSC-Exos) on muscle, dexamethasone-induced muscle atrophy was built both in vitro and in vivo. In the present research, BMSC-Exos attenuated the decrease of myotube diameter induced by dexamethasone, indicating that BMSC-Exos played a protective role in skeletal muscle atrophy. Further mechanism analysis exhibited that the content of miR-486-5p in C2C12 myotubes was up-regulated after treated with BMSC-Exos. Meanwhile, BMSC-Exos markedly downregulated the nuclear translocation of FoxO1, which plays an important role in muscle differentiation and atrophy. Importantly, the miR-486-5p inhibitor reversed the decreased expression of FoxO1 induced by BMSC-Exos. In animal experiments, BMSC-Exos inhibited dexamethasone-induced muscle atrophy, and miR-486-5p inhibitor reversed the protective effect of BMSC-Exos. These results indicating that BMSC-derived exosomes inhibit dexamethasone-induced muscle atrophy via miR486-5p/Foxo1 Axis.
Phylum-Spanning Neuropeptide GPCR Identification and Prioritization: Shaping Drug Target Discovery Pipelines for Nematode Parasite Control
Authors: Atkinson Louise E. , McCoy Ciaran J. , Crooks Bethany A. , McKay Fiona M. , McVeigh Paul , McKenzie Darrin , Irvine Allister , Harrington John , Rosa Bruce A. , Mitreva Makedonka , Marks Nikki J. , Maule Aaron G. , Mousley Angela
Published: September 2021

Nematode parasites undermine human health and global food security. The frontline anthelmintic portfolio used to treat parasitic nematodes is threatened by the escalation of anthelmintic resistance, resulting in a demand for new drug targets for parasite control. Nematode neuropeptide signalling pathways represent an attractive source of novel drug targets which currently remain unexploited. The complexity of the nematode neuropeptidergic system challenges the discovery of new targets for parasite control, however recent advances in parasite ‘omics’ offers an opportunity for the in silico identification and prioritization of targets to seed anthelmintic discovery pipelines. In this study we employed Hidden Markov Model-based searches to identify ~1059 Caenorhabditis elegans neuropeptide G-protein coupled receptor (Ce-NP-GPCR) encoding gene homologs in the predicted protein datasets of 10 key parasitic nematodes that span several phylogenetic clades and lifestyles. We show that, whilst parasitic nematodes possess a reduced complement of Ce-NP-GPCRs, several receptors are broadly conserved across nematode species. To prioritize the most appealing parasitic nematode NP-GPCR anthelmintic targets, we developed a novel in silico nematode parasite drug target prioritization pipeline that incorporates pan-phylum NP-GPCR conservation, C. elegans-derived reverse genetics phenotype, and parasite life-stage specific expression datasets. Several NP-GPCRs emerge as the most attractive anthelmintic targets for broad spectrum nematode parasite control. Our analyses have also identified the most appropriate targets for species- and life stage- directed chemotherapies; in this context we have identified several NP-GPCRs with macrofilaricidal potential. These data focus functional validation efforts towards the most appealing NP-GPCR targets and, in addition, the prioritization strategy employed here provides a blueprint for parasitic nematode target selection beyond NP-GPCRs.
Cortisol and Phosphate Homeostasis: Cushing’s Syndrome Is Associated With Reversible Hypophosphatemia
Authors: Bosman Ariadne , van den Beld Annewieke W. , Feelders Richard A. , Zillikens M. Carola
Published: October 2021

Objectives

The influence of hypercortisolism on phosphate homeostasis is relatively unknown. A few previous studies have reported on patients with Cushing’s syndrome (CS) with hypophosphatemia in whom serum phosphate normalized after initiation of treatment for CS. We aimed to investigate the prevalence of hypophosphatemia in CS, the association between the degree of hypercortisolism and serum phosphate and the change in serum phosphate after remission of CS. We compared the prevalence of hypophosphatemia in CS with the prevalence in the population-based Rotterdam Study (RS).

Methods

Patients diagnosed with CS and treated at the Department of Endocrinology of Erasmus MC in the period of 2002-2020 were included and data was collected on age at diagnosis, sex, serum phosphate, calcium and potassium levels, kidney function and BMI. Using multivariate linear regression, we analyzed the association between 24h urinary free cortisol excretion (UFC) and serum phosphate. Changes in serum phosphate and covariates were tested with a repeated measurement ANOVA, using mean levels of laboratory values for the periods before remission, and 0-14 days and 15-180 days after remission.

Results

Hypophosphatemia before treatment was present in 16% of the 99 CS patients with data on serum phosphate, 24h UFC and covariates. In comparison, the prevalence of hypophosphatemia in RS was 2.0-4.2%. Linear regression showed a negative association between the level of UFC and serum phosphate at diagnosis, which remained significant after adjusting for covariates [β -0.002 (95%CI -0.004; -0.0004), p=0.021]. A subset of 24 patients had additional phosphate measurements at 0-14 days and 15-180 days after remission. In this subgroup, serum phosphate significantly increased from 1.03 ± 0.17 mmol/L prior to remission to 1.22 ± 0.25 mmol/L 15-180 days after remission (p = 0.008). BMI decreased after remission [-1.1 kg/m2, (95%CI -2.09 to -0.07), p=0.037]. Other covariates did not show an equivalent change over time.

Conclusion

In this retrospective study, we found that 16% of patients with CS had hypophosphatemia. Moreover, serum phosphate was related to the level of cortisoluria and increased after remission of CS. Potential underlying mechanisms related to urinary phosphate excretion and possibly involving FGF23, BMI and parathyroid hormone levels should be further explored.
Xanthomatous Hypophysitis: A Case Report and Comprehensive Literature Review
Authors: Zhu Jianyu , Wang Zhicheng , Wang Wenze , Fan Jinghua , Zhang Yi , Li Xiaoxu , Liu Jie , Jiang Shenzhong , Deng Kan , Duan Lian , Yao Yong , Zhu Huijuan
Published: October 2021

Purpose

Xanthomatous hypophysitis (XHP) is an extremely rare form of primary hypophysitis for which there is a lack of clinical experience. A comprehensive understanding of its clinical characteristics, diagnosis and treatment is needed.

Methods

Here, we report a case study and conduct a systematic review of XHP. Thirty-six cases were included, and their clinical manifestations, endocrine assessment, imaging features, treatment and follow-up data were collected and analyzed.

Results

The mean age at diagnosis was 39.1 years, and females were predominant (75.0%). The most common symptom was headache (68.6%), and 66.7% of female patients presented menstrual disorders. The most common pituitary dysfunction was growth hormone (GH) deficiency. More than half of patients exhibited central diabetes insipidus (CDI). The majority of patients had an imaging presentation of a cystic lesion with peripheral enhancement. Pituitary stalk thickening was observed in half of the patients. Total lesion resection was achieved in 57.1% of cases. The recurrence rate after partial resection and biopsy was significantly higher than that after total lesion resection (57.1% vs. 0.0%, P = 0.0147). The most common pituitary hormone abnormalities to resolve after surgery were hyperprolactinemia (100.0%) and GH deficiency (91.7%). The typical pathological feature was inflammatory infiltration of foamy histiocytes, which showed positivity for CD68.

Conclusion

Diagnosis of XHP is difficult when relying on clinical symptoms and imaging features. Therefore, surgical histopathology is necessary. Based on the available evidence, total lesion resection is recommended for treatment. However, the long-term prognosis for this rare disease remains unclear.
Predictive Modeling of MAFLD Based on Hsp90α and the Therapeutic Application of Teprenone in a Diet-Induced Mouse Model
Authors: Xie Yuan , Chen Lu , Xu Zhipeng , Li Chen , Ni Yangyue , Hou Min , Chen Lin , Chang Hao , Yang Yuxuan , Wang Huiquan , He Rongbo , Chen Rourou , Qian Li , Luo Yan , Zhang Ying , Li Na , Zhu Yuxiao , Ji Minjun , Liu Yu
Published: October 2021

Background and Aims

The heat shock protein (Hsp) 90α is induced by stress and regulates inflammation through multiple pathways. Elevated serum Hsp90α had been found in nonalcoholic steatohepatitis (NASH). Geranylgeranylacetone (GGA, also called teprenone) is a terpenoid derivative. It was reported to induce Hsp and alleviate insulin resistance. We aimed to evaluate the Hsp90α as a biomarker in predicting metabolic-associated fatty liver disease (MAFLD) and define the therapeutic effects of geranylgeranylacetone for the disease.

Methods

A clinical study was conducted to analyze the elements associated with Hsp90α, and a predictive model of MAFLD was developed based on Hsp90α. The histopathological correlation between Hsp90α and MAFLD was investigated through a diet-induced mouse model. Furthermore, GGA was applied to the mouse model.

Results

Serum Hsp90α was increased in patients with MAFLD. A positive linear relationship was found between age, glycosylated hemoglobin (HbA1c), MAFLD, and serum Hsp90α. Meanwhile, a negative linear relationship with body mass index (BMI) was found. A model using Hsp90α, BMI, HbA1c, and ALT was established for predicting MAFLD. The area under the receiver operating characteristic (ROC) curves was 0.94 (95% CI 0.909–0.971, p = 0.000). The sensitivity was 84.1%, and the specificity was 93.1%. In vitro experiments, GGA induced Hsp90α in steatosis cells. In the mice model, Hsp90α decreased in the GGA treatment group. Hepatic steatosis, inflammation, insulin resistance, and glucose intolerance were improved in the GGA-treated group. Serum Hsp90α was positively correlated with steatohepatitis activity according to hepatic histopathology.

Conclusions

Serum Hsp90α was elevated in MAFLD, and a positive correlation between serum Hsp90α and the grade of activity of steatohepatitis was observed. The model using BMI, HbA1c, and alanine aminotransferase (ALT) had a good value to predict MAFLD. The findings also revealed the effectiveness of GGA in the treatment of MAFLD.
The Spatio-Temporal Evolution of China’s Hydrogen Fuel Cell Vehicle Innovation Network: Evidence From Patent Citation at Provincial Level
Authors: Yu Pei , Jiang Feng , Cai Zhengfang , Sun Yongping
Published: October 2021

Hydrogen fuel cell vehicle industry is in a rapid development stage. Studying the domestic spatial distribution of hydrogen fuel cell vehicle industry across a country, especially the spatio-temporal evolution of the innovation level and position of each region in innovation network, will help to understand the industry’s development trends and characteristics, and avoid repeated construction. This article uses social network analysis and patent citation information of 2,971 hydrogen fuel cell vehicle related invention patents, owned by 218 micro-innovators across 25 provinces of China from 2001 to 2020, to construct China’s hydrogen fuel cell vehicle innovation network. Based on the dimensions of knowledge production, knowledge consumption, and network broker, the network positions of sample provinces in three periods divided by four main national policies are classified. The main findings are as follows. 1) In China, the total sales of hydrogen fuel cell vehicle and the development of supporting infrastructure are balanced, and a series of national and local industrial development polices have been issued. 2) China’s hydrogen fuel cell vehicle innovation network density, the proportion of universities and research institutes among the innovators, and the active degree of the eastern provinces are all becoming higher. 3) The provinces in optimal network position are all from the eastern region. Shanghai and Liaoning are gradually replaced by Beijing and Jiangsu. 4) Sichuan in the western region is the only network broker based on knowledge consumption. 5) Although Zhejiang, Tianjin, Hebei, Guangdong, and Hubei are not yet in the optimal position, they are outstanding knowledge producers. Specifically, Guangdong is likely to climb to the optimal network position in the next period. The conclusions will help China’s provinces to formulate relevant development policies to optimize industry layout and enhance collaborative innovation in the hydrogen fuel cell vehicle industry.
Be Green to Be Innovative: The Role of Government Subsidies
Authors: Xu Yingbo , Liu Wei , Pu Ruihui , Xu Yonghui
Published: October 2021

Corporate environmental investment has long been recognized as a non-market strategy that helps secure both economic and social benefits. However, we know much less about how environmental investment affects corporate innovation. We argue that investment in environmental protection is an important source of institutional legitimacy for firms to secure government resources, thus providing financial support for corporate innovation activities. Using a sample of Chinese industrial firms, we find that firms investing more in environmental protection can receive more government subsidies and then have better innovation performance. This study emphasizes the mechanism of government resources, which enriches our understanding of the effect of environmental investment on corporate innovation.
Population Genetic Structure of the Invasive Spotted Alfalfa Aphid Therioaphis trifolii (Hemiptera: Aphididae) in China Inferred From Complete Mitochondrial Genomes
Authors: Liu Xinzhi , Wei Shuhua , Du Zhenyong , He Jia , Zhang Xinyue , Li Hu , Zhang Rong , Cai Wanzhi
Published: October 2021

Biological invasions represent a natural rapid evolutionary process in which invasive species may present a major threat to biodiversity and ecosystem integrity. Analyzing the genetic structure and demographic history of invaded populations is critical for the effective management of invasive species. The spotted alfalfa aphid (SAA) Therioaphis trifolii is indigenous in the Mediterranean region of Europe and Africa and has invaded China, causing severe damages to the alfalfa industry. However, little is known about its genetic structure and invasion history. In this study, we obtained 167 complete mitochondrial genome sequences from 23 SAA populations across China based on high-throughput sequencing and performed population genetic and phylogenomic analyses. High haplotype diversity and low nucleotide diversity were found in SAA populations in China with distinct genetic structures, i.e., all populations diverged into three phylogenetic lineages. Demographic history analyses showed a recent expansion of the SAA population, consistent with the recent invasion history. Our study indicated that SAA may have invaded through multiple introduction events during commercial trades of alfalfa, although this needs further validation by nuclear markers.
Newborn Screening for G6PD Deficiency in Xiamen, China: Prevalence, Variant Spectrum, and Genotype-Phenotype Correlations
Authors: Wang Xudong , Xia Zhongmin , He Ying , Zhou Xiaoman , Zhang Haixia , Gao Chunliu , Ge Yunsheng , Cai Xiaofang , Zhou Yulin , Guo Qiwei
Published: October 2021

Background: Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a common inherited enzymatic defect. The purpose of this study was to evaluate the profile of G6PD deficiency and investigate the factors associated with the accuracy of newborn screening (NBS) in Xiamen, China.

Methods: A total of 99,546 newborns were screened by modified fluorescent spot test at the Women and Children’s Hospital, Xiamen University. High-risk neonates were recalled for diagnosis by either a measurement of G6PD activity or genetic testing for the presence of pathogenic G6PD variants using a quantitative G6PD enzymatic assay or the MeltPro® G6PD assay, respectively.

Results: In the first-tier screening, 1,256 newborns were categorized as high risk. Of these, 1,051 were diagnosed with G6PD deficiency, indicating a prevalence of 1.39% in Xiamen, China. Among the 1,013 neonates who underwent genotyping, 851 carried hemizygous, heterozygous, homozygous, or compound heterozygous variants, for a positive predictive value (PPV) of 84.01%. In total, 12 variants and 32 genotypes were identified, and the six most common variants were c.1376G>T, c.1388G>A, c.95A>G, c.1024C>T, c.871G>A, and c.392G>T, which accounted for approximately 94% of the identified alleles. Different variants showed characteristic enzymatic activities, although high phenotypic heterogeneity was observed for each variant. The use of cold-chain transportation significantly improved the PPV of NBS.

Conclusions: We determined the profile of G6PD deficiency in Xiamen, including the prevalence, variant spectrum, and genotype-phenotype correlations and confirmed that maintaining a low temperature during sample transport is essential to ensure the high screening accuracy of NBS. Our data provides epidemiological, genotypic, phenotypic, and clinical practice references to standardize future interventions for G6PD deficiency.
Molecular Characterization Analysis of Thalassemia and Hemoglobinopathy in Quanzhou, Southeast China: A Large-Scale Retrospective Study
Authors: Zhuang Jianlong , Zhang Na , Wang Yuanbai , Zhang Hegan , Zheng Yu , Jiang Yuying , Xie Yingjun , Chen Dongmei
Published: September 2021

Background: There are limited reports available on investigations into the molecular spectrum of thalassemia and hemoglobinopathy in Fujian province, Southeast China. Here, we aim to reveal the spectrum of the thalassemia mutation and hemoglobinopathy in Quanzhou prefecture, Fujian province.

Methods: We collected data from a total of 17,407 subjects with the thalassemia trait in Quanzhou prefecture. Gap-PCR, DNA reverse dot blot hybridization, and DNA sequencing were utilized for common and rare thalassemia gene testing.

Results: In our study, we identified 7,085 subjects who were carrying thalassemia mutations, representing a detection rate of 40.70% (7,085/17,407). Among them, 13 different α-thalassemia gene mutations were detected, with the most common mutation being –SEA (69.01%), followed by –α3.7 (21.34%) and –α4.2 (3.96%). We also discovered 26 β-thalassemia gene mutations, with the mutations of IVS-II-654 (C > T) (36.28%) and CD41/42(–TCTT) (29.16%) being the most prevalent. Besides, a variety of rare thalassemia variants were identified. Among them, the –FIL, βMalay, βIVS–I–130, and βIVS–II–672 mutations were identified in Fujian province for the first time. Additionally, we detected 78 cases of hemoglobinopathies, of which Hb Owari was the first reported case in Fujian province and Hb Miyashiro was the first case identified in the Chinese population.

Conclusion: Our study indicates that there is a diverse range of thalassemia mutations, and it also reveals the mutation spectrum of rare thalassemia and hemoglobinopathies in Quanzhou, Fujian province. It provides valuable data for the prevention and control of thalassemia in Southeast China.
Genomic Insight Into the Population Admixture History of Tungusic-Speaking Manchu People in Northeast China
Authors: Zhang Xianpeng , He Guanglin , Li Wenhui , Wang Yunfeng , Li Xin , Chen Ying , Qu Quanying , Wang Ying , Xi Huanjiu , Wang Chuan-Chao , Wen Youfeng
Published: September 2021

Manchu is the third-largest ethnic minority in China and has the largest population size among the Tungusic-speaking groups. However, the genetic origin and admixture history of the Manchu people are far from clear due to the sparse sampling and a limited number of markers genotyped. Here, we provided the first batch of genome-wide data of genotyping approximate 700,000 single-nucleotide polymorphisms (SNPs) in 93 Manchu individuals collected from northeast China. We merged the newly generated data with data of publicly available modern and ancient East Asians to comprehensively characterize the genetic diversity and fine-scale population structure, as well as explore the genetic origin and admixture history of northern Chinese Manchus. We applied both descriptive methods of ADMIXTURE, fineSTRUCTURE, FST, TreeMix, identity by decedent (IBD), principal component analysis (PCA), and qualitative f-statistics (f3, f4, qpAdm, and qpWave). We found that Liaoning Manchus have a close genetic relationship and significant admixture signal with northern Han Chinese, which is in line with the cluster patterns in the haplotype-based results. Additionally, the qpAdm-based admixture models showed that modern Manchu people were formed as major ancestry related to Yellow River farmers and minor ancestry linked to ancient populations from Amur River Bain, or others. In summary, the northeastern Chinese Manchu people in Liaoning were an exception to the coherent genetic structure of Tungusic-speaking populations, probably due to the large-scale population migrations and genetic admixtures in the past few hundred years.
Genome-Wide Identification and Low-Temperature Expression Analysis of bHLH Genes in Prunus mume
Authors: Ding Aiqin , Ding Anqi , Li Ping , Wang Jia , Cheng Tangren , Bao Fei , Zhang Qixiang
Published: October 2021

Prunus mume is an illustrious ornamental woody plant with colorful flowers, delicate fragrances, and graceful tree forms. Low temperature limits its geographical distribution. The basic helix-loop-helix (bHLH) proteins exist in most eukaryotes as a transcription factor superfamily, which play a crucial role in metabolism, physiology, development, and response to various stresses of higher organisms. However, the characteristics of the bHLH gene family and low-temperature response remain unknown in P. mume. In the present study, we distinguished 95 PmbHLH genes in the P. mume whole-genome and analyzed their features. PmbHLHs were divided into 23 subfamilies and one orphan by phylogenetic analysis. Similar gene structures and conserved motifs appeared in the same subfamily. These genes were situated in eight chromosomes and scaffolds. Gene duplication events performed a close relationship to P. mume, P. persica, and P. avium. Tandem duplications probably promoted the expansion of PmbHLHs. According to predicted binding activities, the PmbHLHs were defined as the Non-DNA-binding proteins and DNA-binding proteins. Furthermore, PmbHLHs exhibited tissue-specific and low-temperature induced expression patterns. By analyzing transcriptome data, 10 PmbHLHs which are responsive to low-temperature stress were selected. The qRT-PCR results showed that the ten PmbHLH genes could respond to low-temperature stress at different degrees. There were differences in multiple variations among different varieties. This study provides a basis to research the evolution and low-temperature tolerance of PmbHLHs, and might enhance breeding programs of P. mume by improving low-temperature tolerance.