bluuebunny/crossref_metadata_2025 huggingface dataset:
Genome-Wide Analysis of the Fatty Acid Desaturase Gene Family Reveals the Key Role of PfFAD3 in α-Linolenic Acid Biosynthesis in Perilla Seeds
Authors: Duan Wu , Shi-Mei Yang , Zhi-Wei Shang , Jing Xu , De-Gang Zhao , Hong-Bin Wang , Qi Shen
Published: November 2021

Perilla (Perilla frutescens), a traditional medicinal and oilseed crop in Asia, contains extremely high levels of polyunsaturated α-linolenic acid (ALA) (up to 60.9%) in its seeds. ALA biosynthesis is a multistep process catalyzed by fatty acid desaturases (FADs), but the FAD gene family in perilla has not been systematically characterized. Here, we identified 42 PfFADs in the perilla genome and classified them into five subfamilies. Subfamily members of PfFADs had similar exon/intron structures, conserved domain sequences, subcellular localizations, and cis-regulatory elements in their promoter regions. PfFADs also possessed various expression patterns. PfFAD3.1 was highly expressed in the middle stage of seed development, whereas PfFAD7/8.3 and PfFAD7/8.5 were highly expressed in leaf and later stages of seed development, respectively. Phylogenetic analysis revealed that the evolutionary features coincided with the functionalization of different subfamilies of PUFA desaturase. Heterologous overexpression of PfFAD3.1 in Arabidopsis thaliana seeds increased ALA content by 17.68%–37.03%. These findings provided insights into the characteristics and functions of PfFAD genes in perilla.
Natural SINEUP RNAs in Autism Spectrum Disorders: RAB11B-AS1 Dysregulation in a Neuronal CHD8 Suppression Model Leads to RAB11B Protein Increase
Authors: Zarantonello Giulia , Arnoldi Michele , Filosi Michele , Tebaldi Toma , Spirito Giovanni , Barbieri Anna , Gustincich Stefano , Sanges Remo , Domenici Enrico , Di Leva Francesca , Biagioli Marta
Published: November 2021

CHD8 represents one of the highest confidence genetic risk factors implied in Autism Spectrum Disorders, with most mutations leading to CHD8 haploinsufficiency and the insurgence of specific phenotypes, such as macrocephaly, facial dysmorphisms, intellectual disability, and gastrointestinal complaints. While extensive studies have been conducted on the possible consequences of CHD8 suppression and protein coding RNAs dysregulation during neuronal development, the effects of transcriptional changes of long non-coding RNAs (lncRNAs) remain unclear. In this study, we focused on a peculiar class of natural antisense lncRNAs, SINEUPs, that enhance translation of a target mRNA through the activity of two RNA domains, an embedded transposable element sequence and an antisense region. By looking at dysregulated transcripts following CHD8 knock down (KD), we first identified RAB11B-AS1 as a potential SINEUP RNA for its domain configuration. Then we demonstrated that such lncRNA is able to increase endogenous RAB11B protein amounts without affecting its transcriptional levels. RAB11B has a pivotal role in vesicular trafficking, and mutations on this gene correlate with intellectual disability and microcephaly. Thus, our study discloses an additional layer of molecular regulation which is altered by CHD8 suppression. This represents the first experimental confirmation that naturally occurring SINEUP could be involved in ASD pathogenesis and underscores the importance of dysregulation of functional lncRNAs in neurodevelopment.
Wnt1 Lineage Specific Deletion of Gpr161 Results in Embryonic Midbrain Malformation and Failure of Craniofacial Skeletal Development
Authors: Kim Sung-Eun , Robles-Lopez Karla , Cao Xuanye , Liu Kristyn , Chothani Pooja J. , Bhavani Nikitha , Rahman Lauren , Mukhopadhyay Saikat , Wlodarczyk Bogdan J. , Finnell Richard H.
Published: November 2021

Sonic hedgehog (Shh) signaling regulates multiple morphogenetic processes during embryonic neurogenesis and craniofacial skeletal development. Gpr161 is a known negative regulator of Shh signaling. Nullizygous Gpr161 mice are embryonic lethal, presenting with structural defects involving the neural tube and the craniofacies. However, the lineage specific role of Gpr161 in later embryonic development has not been thoroughly investigated. We studied the Wnt1-Cre lineage specific role of Gpr161 during mouse embryonic development. We observed three major gross morphological phenotypes in Gpr161 cKO (Gpr161 f/f; Wnt1-Cre) fetuses; protrusive tectum defect, encephalocele, and craniofacial skeletal defect. The overall midbrain tissues were expanded and cell proliferation in ventricular zones of midbrain was increased in Gpr161 cKO fetuses, suggesting that protrusive tectal defects in Gpr161 cKO are secondary to the increased proliferation of midbrain neural progenitor cells. Shh signaling activity as well as upstream Wnt signaling activity were increased in midbrain tissues of Gpr161 cKO fetuses. RNA sequencing further suggested that genes in the Shh, Wnt, Fgf and Notch signaling pathways were differentially regulated in the midbrain of Gpr161 cKO fetuses. Finally, we determined that cranial neural crest derived craniofacial bone formation was significantly inhibited in Gpr161 cKO fetuses, which partly explains the development of encephalocele. Our results suggest that Gpr161 plays a distinct role in midbrain development and in the formation of the craniofacial skeleton during mouse embryogenesis.
Mitochondrial-Linked De Novo Pyrimidine Biosynthesis Dictates Human T-Cell Proliferation but Not Expression of Effector Molecules
Authors: Peeters Marlies J. W. , Aehnlich Pia , Pizzella Adriano , Mølgaard Kasper , Seremet Tina , Met Özcan , Rasmussen Lene Juel , thor Straten Per , Desler Claus
Published: November 2021

T-cell activation upon antigen stimulation is essential for the continuation of the adaptive immune response. Impairment of mitochondrial oxidative phosphorylation is a well-known disruptor of T-cell activation. Dihydroorotate dehydrogenase (DHODH) is a component of the de novo synthesis of pyrimidines, the activity of which depends on functional oxidative phosphorylation. Under circumstances of an inhibited oxidative phosphorylation, DHODH becomes rate-limiting. Inhibition of DHODH is known to block clonal expansion and expression of effector molecules of activated T cells. However, this effect has been suggested to be caused by downstream impairment of oxidative phosphorylation rather than a lower rate of pyrimidine synthesis. In this study, we successfully inhibit the DHODH of T cells with no residual effect on oxidative phosphorylation and demonstrate a dose-dependent inhibition of proliferation of activated CD3+ T cells. This block is fully rescued when uridine is supplemented. Inhibition of DHODH does not alter expression of effector molecules but results in decreased intracellular levels of deoxypyrimidines without decreasing cell viability. Our results clearly demonstrate the DHODH and mitochondrial linked pyrimidine synthesis as an independent and important cytostatic regulator of activated T cells.
Exploring the Prognostic Value, Immune Implication and Biological Function of H2AFY Gene in Hepatocellular Carcinoma
Authors: Huang Yongbiao , Huang Shanshan , Ma Li , Wang Yali , Wang Xi , Xiao Lingyan , Qin Wan , Li Long , Yuan Xianglin
Published: November 2021

Background

Hepatocellular carcinoma (HCC) is an extremely malignant cancer with poor survival. H2AFY gene encodes for a variant of H2A histone, and it has been found to be dysregulated in various tumors. However, the clinical value, biological functions and correlations with immune infiltration of H2AFY in HCC remain unclear.

Methods

We analyzed the expression and clinical significance of H2AFY in HCC using multiple databases, including Oncomine, HCCDB, TCGA, ICGC, and so on. The genetic alterations of H2AFY were analyzed by cBioPortal and COSMIC databases. Co-expression networks of H2AFY and its regulators were investigated by LinkedOmics. The correlations between H2AFY and tumor immune infiltration were explored using TIMER, TISIDB databases, and CIBERSORT method. Finally, H2AFY was knocked down with shRNA lentiviruses in HCC cell lines for functional assays in vitro.

Results

H2AFY expression was upregulated in the HCC tissues and cells. Kaplan–Meier and Cox regression analyses revealed that high H2AFY expression was an independent prognostic factor for poor survival in HCC patients. Functional network analysis indicated that H2AFY and its co-expressed genes regulates cell cycle, mitosis, spliceosome and chromatin assembly through pathways involving many cancer-related kinases and E2F family. Furthermore, we observed significant correlations between H2AFY expression and immune infiltration in HCC. H2AFY knockdown suppressed the cell proliferation and migration, promoted cycle arrest, and apoptosis of HCC cells in vitro.

Conclusion

Our study revealed that H2AFY is a potential biomarker for unfavorable prognosis and correlates with immune infiltration in HCC.
Computational Construction of a Single-Chain Bi-Paratopic Antibody Allosterically Inhibiting TCR-Staphylococcal Enterotoxin B Binding
Authors: Bai Ganggang , Ge Yanhong , Su Yuhong , Chen Shuo , Zeng Xingcheng , Lu Huixia , Ma Buyong
Published: November 2021

Staphylococcal enterotoxin B (SEB) simultaneously crosslinks MHC class II antigen and TCR, promoting proliferation of T cells and releasing a large number of toxic cytokines. In this report, we computationally examined the possibility of using a single-chain biparatopic bispecific antibody to target SEB and prevent TCR binding. The design was inspired by the observation that mixing two anti-SEB antibodies 14G8 and 6D3 can block SEB-TCR activation, and we used 14G8-6D3-SEB tertiary crystal structure as a template. Twelve simulation systems were constructed to systematically examine the effects of the designed bispecific scFV MB102a, including isolated SEB, MB102a with different linkers, MB102a-SEB complex, MB102a-SEB-TCRβ complex, MB102a-SEB-TCR-MHC II complex, and MB102a-SEB-MHC II. Our all atom molecular dynamics simulations (total 18,900 ns) confirmed that the designed single-chain bispecific antibody may allosterically prevent SEB-TCRβ chain binding and inhibit SEB-TCR-MHC II formation. Subsequent analysis indicated that the binding of scFV to SEB correlates with SEB-TCR binding site motion and weakens SEB-TCR interactions.
Interferon Lambda Signaling in Macrophages Is Necessary for the Antiviral Response to Influenza
Authors: Mallampalli Rama K. , Adair Jessica , Elhance Ajit , Farkas Daniela , Chafin Lexie , Long Matthew E. , De Mithu , Mora Ana L. , Rojas Mauricio , Peters Victor , Bednash Joseph S. , Tsai MuChun , Londino James D.
Published: November 2021

Interferon lambda (IFNλ) signaling is a promising therapeutic target against viral infection in murine models, yet little is known about its molecular regulation and its cognate receptor, interferon lambda receptor 1 (IFNLR1) in human lung. We hypothesized that the IFNλ signaling axis was active in human lung macrophages. In human alveolar macrophages (HAMs), we observed increased IFNLR1 expression and robust increase in interferon-stimulated gene (ISG) expression in response to IFNλ ligand. While human monocytes express minimal IFNLR1, differentiation of monocytes into macrophages with macrophage colony-stimulating factor (M-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF) increased IFNLR1 mRNA, IFNLR1 protein expression, and cellular response to IFNλ ligation. Conversely, in mice, M-CSF or GM-CSF stimulated macrophages failed to produce ISGs in response to related ligands, IFNL2 or IFNL3, suggesting that IFNLR1 signaling in macrophages is species-specific. We next hypothesized that IFNλ signaling was critical in influenza antiviral responses. In primary human airway epithelial cells and precision-cut human lung slices, influenza infection substantially increased IFNλ levels. Pretreatment of both HAMs and differentiated human monocytes with IFNL1 significantly inhibited influenza infection. IFNLR1 knockout in the myeloid cell line, THP-1, exhibited reduced interferon responses to either direct or indirect exposure to influenza infection suggesting the indispensability of IFNLR1 for antiviral responses. These data demonstrate the presence of IFNλ - IFNLR1 signaling axis in human lung macrophages and a critical role of IFNλ signaling in combating influenza infection.
Risk Factors and Brain Metabolic Mechanism of Sleep Disorders in Autoimmune Encephalitis
Authors: Liu Xiao , Yu Tingting , Zhao Xiaobin , Yu Ping , Lv Ruijuan , Wang Chunxue , Ai Lin , Wang Qun
Published: November 2021

Background

Sleep disorders (SDs) in autoimmune encephalitis (AE) have received little attention and are poorly understood. We investigated the clinical characteristics, risk factors, and cerebral metabolic mechanism of SD in AE.

Methods

Clinical, laboratory, and imaging data were retrospectively reviewed in 121 consecutively patients with definite AE. The risk factors for SD in AE were estimated by logistic regression analysis. Group comparisons based on 18F-fluorodeoxy-glucose positron emission tomography (18F-FDG-PET) data were made between patients with and without SD, to further analyze potential brain metabolic mechanism of SD in AE.

Results

A total of 52.9% patients (64/121) with SD were identified. The multivariate logistic model analysis showed that smoking [odds ratio (OR), 6.774 (95% CI, 1.238–37.082); p = 0.027], increased Hamilton Depression scale (HAMD) score [OR, 1.074 (95% CI, 1.002–1.152); p = 0.045], hyperhomocysteinemia [OR, 2.815 (95% CI, 1.057–7.496); p = 0.038], elevated neuron-specific enolase (NSE) level [OR, 1.069 (95% CI, 1.007–1.135); p = 0.03] were independently correlated with higher risk of SD in AE patients. Contrastingly, high MoCA score [OR, 0.821 (95% CI, 0.752–0.896); p < 0.001] was associated with lower risk of SD in AE subjects. Compared to controls, AE patients had less total sleep time, less sleep efficiency, longer sleep latency, more wake, higher percent of stage N1, lower percent of stage N3 and rapid eye movement, and more arousal index in non-rapid eye movement sleep (p < 0.05 for all). Voxel-based group comparison analysis showed that, compared to patients without SD, patients with SD had increased metabolism in the basal ganglia, cerebellum, brainstem, median temporal lobe, thalamus, and hypothalamus [p < 0.05, false discovery rate (FDR) corrected]; decreased metabolism in superior frontal gyrus, medial frontal gyrus, and posterior cingulate cortex (p < 0.001, uncorrected). These results were confirmed by region of interest-based analysis between PET and sleep quality.

Conclusion

Smoking, increased HAMD score, hyperhomocysteinemia, and elevated NSE level were correlated with higher risk of SD. High MoCA score was associated with lower risk of SD in AE subjects. Moreover, a widespread metabolic network dysfunction may be involved in the pathological mechanism of SD in AE.
Efficacy and Safety of Iguratimod Supplement to the Standard Immunosuppressive Regimen in Highly Mismatched Renal Transplant Recipients: A Pilot Study
Authors: Tao Jun , Sun Li , Wang Zijie , Chen Hao , Han Zhijian , Zhang Hengcheng , Yang Haiwei , Huang Zhengkai , Fei Shuang , Ju Xiaobin , Tan Ruoyun , Gu Min
Published: November 2021

Iguratimod (IGU) can mitigate the symptoms of rheumatoid arthritis through its anti-inflammatory effects. The objective of this study was to investigate the clinical efficacy and safety of IGU in highly HLA-mismatched renal transplant recipients, in combination with standard immunosuppressive regimen. This pilot study was designed as an open-label, blank-control, randomized clinical trial on patients recruited from a single transplant center in China. Patients who met the inclusion criteria were randomized to the IGU (n=27) and blank control (n=27) groups. IGU was administrated with the conventional triple immunosuppressive protocol for 52 weeks after kidney transplantation. The incidence of biopsy-proven acute rejection rate was 14.8% (4/27) in the IGU group and 29.6% (8/27) in the control group, P = 0.19. The clinical rejection rate was also substantially reduced in the IGU group (3.7% vs. 18.5%, P = 0.08). De novo donor-specific antibody also showed a decline trend in the IGU group after 52 weeks. The graft function and incidence of adverse events were similar between the two groups. In addition, IGU intervention significantly decreased the number of NK cells throughout the follow-up. In conclusion, our study has shown the possibility that IGU could reduce the allograft rejection rate and de novo DSA with appreciable safety in combination with conventional immunosuppressants. Formal clinical trials were warranted based on current findings.
Transcriptomic Profiling Reveals a Role for TREM-1 Activation in Enterovirus D68 Infection-Induced Proinflammatory Responses
Authors: Li Jinyu , Yang Shan , Liu Sihua , Chen Yulu , Liu Hongyun , Su Yazhi , Liu Ruicun , Cui Yujun , Song Yajun , Teng Yue , Wang Tao
Published: November 2021

Increasing cases related to the pathogenicity of Enterovirus D68 (EV-D68) have made it a growing worldwide public health concern, especially due to increased severe respiratory illness and acute flaccid myelitis (AFM) in children. There are currently no vaccines or medicines to prevent or treat EV-D68 infections. Herein, we performed genome-wide transcriptional profiling of EV-D68-infected human rhabdomyosarcoma (RD) cells to investigate host-pathogen interplay. RNA sequencing and subsequent experiments revealed that EV-D68 infection induced a profound transcriptional dysregulation of host genes, causing significantly elevated inflammatory responses and altered antiviral immune responses. In particular, triggering receptor expressed on myeloid cells 1 (TREM-1) is involved in highly activated TREM-1 signaling processes, acting as an important mediator in EV-D68 infection, and it is related to upregulation of interleukin 8 (IL-8), IL-6, IL-12p70, IL-1β, and tumor necrosis factor alpha (TNF-α). Further results demonstrated that NF-κB p65 was essential for EV-D68-induced TREM-1 upregulation. Moreover, inhibition of the TREM1 signaling pathway by the specific inhibitor LP17 dampened activation of the p38 mitogen-activated protein kinase (MAPK) signaling cascade, suggesting that TREM-1 mainly transmits activation signals to phosphorylate p38 MAPK. Interestingly, treatment with LP17 to inhibit TREM-1 inhibited viral replication and infection. These findings imply the pathogenic mechanisms of EV-D68 and provide critical insight into therapeutic intervention in enterovirus diseases.
Characterization of Pathogenesis and Inflammatory Responses to Experimental Parechovirus Encephalitis
Authors: Jan Ming-Wei , Su Hong-Lin , Chang Tsung-Hsien , Tsai Kuen-Jer
Published: November 2021

Human parechovirus type 3 (PeV-A3) infection has been recognized as an emerging etiologic factor causing severe nerve disease or sepsis in infants and young children. But the neuropathogenic mechanisms of PeV-A3 remain unknown. To understand the pathogenesis of PeV-A3 infection in the neuronal system, PeV-A3-mediated cytopathic effects were analyzed in human glioblastoma cells and neuroblastoma cells. PeV-A3 induced interferons and inflammatory cytokine expression in these neuronal cells. The pronounced cytopathic effects accompanied with activation of death signaling pathways of apoptosis, autophagy, and pyroptosis were detected. A new experimental disease model of parechovirus encephalitis was established. In the disease model, intracranial inoculation with PeV-A3 in C57BL/6 neonatal mice showed body weight loss, hindlimb paralysis, and approximately 20% mortality. PeV-A3 infection in the hippocampus and cortex regions of the neonatal mouse brain was revealed. Mechanistic assay supported the in vitro results, indicating detection of PeV-A3 replication, inflammatory cytokine expression, and death signaling transduction in mouse brain tissues. These in vitro and in vivo studies revealed that the activation of death signaling and inflammation responses is involved in PeV-A3-mediated neurological disorders. The present results might account for some of the PeV-A3-associated clinical manifestations.
Interleukin-36 Cytokines in Infectious and Non-Infectious Lung Diseases
Authors: Peñaloza Hernán F. , van der Geest Rick , Ybe Joel A. , Standiford Theodore J. , Lee Janet S.
Published: November 2021

The IL-36 family of cytokines were identified in the early 2000’s as a new subfamily of the IL-1 cytokine family, and since then, the role of IL-36 cytokines during various inflammatory processes has been characterized. While most of the research has focused on the role of these cytokines in autoimmune skin diseases such as psoriasis and dermatitis, recent studies have also shown the importance of IL-36 cytokines in the lung inflammatory response during infectious and non-infectious diseases. In this review, we discuss the biology of IL-36 cytokines in terms of how they are produced and activated, as well as their effects on myeloid and lymphoid cells during inflammation. We also discuss the role of these cytokines during lung infectious diseases caused by bacteria and influenza virus, as well as other inflammatory conditions in the lungs such as allergic asthma, lung fibrosis, chronic obstructive pulmonary disease, cystic fibrosis and cancer. Finally, we discuss the current therapeutic advances that target the IL-36 pathway and the possibility to extend these tools to treat lung inflammatory diseases.
SIRT1: A Potential Therapeutic Target in Autoimmune Diseases
Authors: Shen Pan , Deng Xuan , Chen Zhe , Ba Xin , Qin Kai , Huang Ying , Huang Yao , Li Tingting , Yan Jiahui , Tu Shenghao
Published: November 2021

The morbidity and mortality of autoimmune diseases (Ads) have been increasing worldwide, and the identification of novel therapeutic strategies for prevention and treatment is urgently needed. Sirtuin 1 (SIRT1), a member of the class III family of nicotinamide adenine dinucleotide (NAD+)-dependent histone deacetylases, has been reported to participate in the progression of several diseases. SIRT1 also regulates inflammation, oxidative stress, mitochondrial function, immune responses, cellular differentiation, proliferation and metabolism, and its altered functions are likely involved in Ads. Several inhibitors and activators have been shown to affect the development of Ads. SIRT1 may represent a novel therapeutic target in these diseases, and small molecules or natural products that modulate the functions of SIRT1 are potential therapeutic agents. In the present review, we summarize current studies of the biological functions of SIRT1 and its role in the pathogenesis and treatment of Ads.
hPMSCs-Derived Exosomal miRNA-21 Protects Against Aging-Related Oxidative Damage of CD4+ T Cells by Targeting the PTEN/PI3K-Nrf2 Axis
Authors: Xiong Yanlian , Xiong Yanlei , Zhang Hengchao , Zhao Yaxuan , Han Kaiyue , Zhang Jiashen , Zhao Dongmei , Yu Zhenhai , Geng Ziran , Wang Longfei , Wang Yueming , Luan Xiying
Published: November 2021

Mesenchymal stem cells (MSCs)-derived exosomes were considered a novel therapeutic approach in many aging-related diseases. This study aimed to clarify the protective effects of human placenta MSCs-derived exosomes (hPMSC-Exo) in aging-related CD4+ T cell senescence and identified the underlying mechanisms using a D-gal induced mouse aging model. Senescent T cells were detected SA-β-gal stain. The degree of DNA damage was evaluated by detecting the level of 8-OH-dG. The superoxide dismutase (SOD) and total antioxidant capacity (T-AOC) activities were measured. The expression of aging-related proteins and senescence-associated secretory phenotype (SASP) were detected by Western blot and RT-PCR. We found that hPMSC-Exo treatment markedly decreased oxidative stress damage (ROS and 8-OH-dG), SA-β-gal positive cell number, aging-related protein expression (p53 and γ-H2AX), and SASP expression (IL-6 and OPN) in senescent CD4+ T cells. Additionally, hPMSC-Exo containing miR-21 effectively downregulated the expression of PTEN, increased p-PI3K and p-AKT expression, and Nrf2 nuclear translocation and the expression of downstream target genes (NQO1 and HO-1) in senescent CD4+ T cells. Furthermore, in vitro studies uncovered that hPMSC-Exo attenuated CD4+ T cell senescence by improving the PTEN/PI3K-Nrf2 axis by using the PTEN inhibitor bpV (HOpic). We also validated that PTEN was a target of miR-21 by using a luciferase reporter assay. Collectively, the obtained results suggested that hPMSC-Exo attenuates CD4+ T cells senescence via carrying miRNA-21 and activating PTEN/PI3K-Nrf2 axis mediated exogenous antioxidant defenses.
Programmed Cell Death Pathways in the Pathogenesis of Idiopathic Inflammatory Myopathies
Authors: Shi Jia , Tang Mingwei , Zhou Shuang , Xu Dong , Zhao Jiuliang , Wu Chanyuan , Wang Qian , Tian Xinping , Li Mengtao , Zeng Xiaofeng
Published: November 2021

Idiopathic inflammatory myopathy (IIM) is a heterogeneous group of acquired, autoimmune muscle diseases characterized by muscle inflammation and extramuscular involvements. Present literatures have revealed that dysregulated cell death in combination with impaired elimination of dead cells contribute to the release of autoantigens, damage-associated molecular patterns (DAMPs) and inflammatory cytokines, and result in immune responses and tissue damages in autoimmune diseases, including IIMs. This review summarizes the roles of various forms of programmed cell death pathways in the pathogenesis of IIMs and provides evidence for potential therapeutic targets.
Endocrinopathies in Inborn Errors of Immunity
Authors: Takasawa Kei , Kanegane Hirokazu , Kashimada Kenichi , Morio Tomohiro
Published: November 2021

Inborn errors of immunity (IEI), caused by hereditary or genetic defects, are a group of more than 400 disorders, in which the immune system, including lymphocytes, neutrophils, macrophages, and complements, does not function properly. The endocrine system is frequently affected by IEI as an associated clinical feature and a complex network of glands which regulate many important body functions, including growth, reproduction, homeostasis, and energy regulation. Most endocrine disorders associated with IEI are hypofunction which would be treated with supplementation therapy, and early diagnosis and appropriate management are essential for favorable long-term outcomes in patients with IEI. In this review, we aimed to comprehensively summarize and discuss the current understanding on the clinical features and the pathophysiology of endocrine disorders in IEI. This review is composed with three parts. First, we discuss the two major pathophysiology of endocrinopathy in IEI, autoimmune response and direct effects of the responsible genes. Next, the details of each endocrinopathy, such as growth failure, hypothyroidism, hypoparathyroidism, adrenal insufficiency, diabetes mellitus (DM) are specified. We also illustrated potential endocrinopathy due to hematopoietic stem cell transplantation, including hypogonadism and adrenal insufficiency due to glucocorticoid therapy.
Intercepting Premalignant, Preinvasive Breast Lesions Through Vaccination
Authors: Zachariah Nadia Nocera , Basu Amrita , Gautam Namrata , Ramamoorthi Ganesan , Kodumudi Krithika N. , Kumar Nagi B. , Loftus Loretta , Czerniecki Brian J.
Published: November 2021

Breast cancer (BC) prevention remains the ultimate cost-effective method to reduce the global burden of invasive breast cancer (IBC). To date, surgery and chemoprevention remain the main risk-reducing modalities for those with hereditary cancer syndromes, as well as high-risk non-hereditary breast lesions such as ADH, ALH, or LCIS. Ductal carcinoma in situ (DCIS) is a preinvasive malignant lesion of the breast that closely mirrors IBC and, if left untreated, develops into IBC in up to 50% of lesions. Certain high-risk patients with DCIS may have a 25% risk of developing recurrent DCIS or IBC, even after surgical resection. The development of breast cancer elicits a strong immune response, which brings to prominence the numerous advantages associated with immune-based cancer prevention over drug-based chemoprevention, supported by the success of dendritic cell vaccines targeting HER2-expressing BC. Vaccination against BC to prevent or interrupt the process of BC development remains elusive but is a viable option. Vaccination to intercept preinvasive or premalignant breast conditions may be possible by interrupting the expression pattern of various oncodrivers. Growth factors may also function as potential immune targets to prevent breast cancer progression. Furthermore, neoantigens also serve as effective targets for interception by virtue of strong immunogenicity. It is noteworthy that the immune response also needs to be strong enough to result in target lesion elimination to avoid immunoediting as it may occur in IBC arising from DCIS. Overall, if the issue of vaccine targets can be solved by interrupting premalignant lesions, there is a potential to prevent the development of IBC.
Air-Sea CO2 Exchange in the Strait of Gibraltar
Authors: Curbelo-Hernández David , Santana-Casiano J. Magdalena , González Aridane González , González-Dávila Melchor
Published: November 2021

The seasonal and spatial variability of the CO2 system and air-sea fluxes were studied in surface waters of the Strait of Gibraltar between February 2019 and March 2021. High-resolution data was collected by a surface ocean observation platform aboard a volunteer observing ship. The CO2 system was strongly influenced by temperature and salinity fluctuations forced by the seasonal and spatial variability in the depth of the Atlantic–Mediterranean Interface layer and by the tidal and wind-induced upwelling. The changes in seawater CO2 fugacity (fCO2,sw) and fluxes were mainly driven by temperature despite the significant influence of non-thermal processes in the southernmost part. The thermal to non-thermal effect ratio (T/B) reached maximum values in the northern section (>1.8) and minimum values in the southern section (<1.30). The fCO2,sw increased with temperature by 9.02 ± 1.99 μatm °C–1 (r2 = 0.86 and ρ = 0.93) and 4.51 ± 1.66 μatm °C–1 (r2 = 0.48 and ρ = 0.69) in the northern and southern sections, respectively. The annual cycle of total inorganic carbon normalized to a constant salinity of 36.7 (NCT) was assessed. Net community production processes described 93.5–95.6% of the total NCT change, while air-sea exchange and horizontal and vertical advection accounted for <4.6%. The fCO2,sw in the Strait of Gibraltar since 1999 has been fitted to an equation with an interannual trend of 2.35 ± 0.06 μatm year–1 and a standard error of estimate of ±12.8 μatm. The seasonality of the air-sea CO2 fluxes reported the behavior as a strong CO2 sink during the cold months and as a weak CO2 source during the warm months. Both the northern and the southern sections acted as a net CO2 sink of −0.82 and −1.01 mol C m–2 year–1, respectively. The calculated average CO2 flux for the entire area was −7.12 Gg CO2 year–1 (−1.94 Gg C year–1).
Conditional Survival of Advanced Epithelial Ovarian Cancer: A Real-World Data Retrospective Cohort Study From the SEER Database
Authors: Zheng Peng , Zheng Ping , Chen Guilin
Published: November 2021

Objective: To analyze conditional survival (CS) in patients with advanced epithelial ovarian cancer (EOC) and investigate prognostic factors that affect the CS rate to provide more accurate survival information.

Methods: Patients with advanced EOC between 2004 and 2015 were identified from the Surveillance, Epidemiology, and End Results (SEER) database. CS analysis was performed to depict exact survival for patients who had already survived a specific number of years. Cox proportional hazards regression was performed to ascertain the individual contribution of factors associated with actuarial overall survival (OS) at diagnosis and CS at 1, 3, and 5 years after diagnosis.

Results: Of 11,773 patients, OS decreased from 32.2% at 6 years to 25.1% at 8 years, while the corresponding 5 year CS (CS5) increased from 37.5% at 1 year to 43.9% at 3 years. Subgroup analysis stratified by clinicopathological characteristics showed that CS5 was always higher than the corresponding actuarial survival (all Δ > 0). Based on multivariate analysis at diagnosis, age, race, marital status, histological type, tumor grade, size, T stage, M stage, surgery, radiation therapy, and chemotherapy were independent prognostic factors for OS. Five years after diagnosis, however, only age, histological type, tumor grade, and laterality were persistently significant independent prognostic factors (all P <0.05). Furthermore, patients with poor pathological prognostic factors achieved greater improvements in CS5 rates, and the survival gaps between OS and CS were more obvious.

Conclusion: CS of advanced EOC was dynamic and increased over time. Age, histology, tumor grade, and laterality were significant prognostic factors even 5 years after diagnosis. Thus, the availability of updated prognoses at various time points will allow clinicians to better guide their patients.
Exercise for Neuropathic Pain: A Systematic Review and Expert Consensus
Authors: Zhang Yong-Hui , Hu Hao-Yu , Xiong Yuan-Chang , Peng Changgeng , Hu Li , Kong Ya-Zhuo , Wang Yu-Ling , Guo Jia-Bao , Bi Sheng , Li Tie-Shan , Ao Li-Juan , Wang Chu-Huai , Bai Yu-Long , Fang Lei , Ma Chao , Liao Lin-Rong , Liu Hao , Zhu Yi , Zhang Zhi-Jie , Liu Chun-Long , Fang Guo-En , Wang Xue-Qiang
Published: November 2021

Background: Neuropathic pain (NP), a severe and disruptive symptom following many diseases, normally restricts patients' physical functions and leads to anxiety and depression. As an economical and effective therapy, exercise may be helpful in NP management. However, few guidelines and reviews focused on exercise therapy for NP associated with specific diseases. The study aimed to summarize the effectiveness and efficacy of exercise for various diseases with NP supported by evidence, describe expert recommendations for NP from different causes, and inform policymakers of the guidelines.

Design: A systematic review and expert consensus.

Methods: A systematic search was conducted in PubMed. We included systematic review and meta-analysis, randomized controlled trials (RCTs), which assessed patients with NP. Studies involved exercise intervention and outcome included pain intensity at least. Physiotherapy Evidence Database and the Assessment of Multiple Systematic reviews tool were used to grade the quality assessment of the included RCTs and systematic reviews, respectively. The final grades of recommendation were based on strength of evidence and a consensus discussion of results of Delphi rounds by the Delphi consensus panel including 21 experts from the Chinese Association of Rehabilitation Medicine.

Results: Eight systematic reviews and 21 RCTs fulfilled all of the inclusion criteria and were included, which were used to create the 10 evidence-based consensus statements. The 10 expert recommendations regarding exercise for NP symptoms were relevant to the following 10 different diseases: spinal cord injury, stroke, multiple sclerosis, Parkinson's disease, cervical radiculopathy, sciatica, diabetic neuropathy, chemotherapy-induced peripheral neuropathy, HIV/AIDS, and surgery, respectively. The exercise recommended in the expert consensus involved but was not limited to muscle stretching, strengthening/resistance exercise, aerobic exercise, motor control/stabilization training and mind-body exercise (Tai Chi and yoga).

Conclusions: Based on the available evidence, exercise is helpful to alleviate NP intensity. Therefore, these expert consensuses recommend that proper exercise programs can be considered as an effective alternative treatment or complementary therapy for most patients with NP. The expert consensus provided medical staff and policymakers with applicable recommendations for the formulation of exercise prescription for NP. This consensus statement will require regular updates after five–ten years.
Nematicidal Activity of Cyclopiazonic Acid Derived From Penicillium commune Against Root-Knot Nematodes and Optimization of the Culture Fermentation Process
Authors: Nguyen Van Thi , Yu Nan Hee , Lee Yookyung , Hwang In Min , Bui Hung Xuan , Kim Jin-Cheol
Published: November 2021

Among 200 fungal strains isolated from the soil, only one culture filtrate of Aspergillus flavus JCK-4087 showed strong nematicidal activity against Meloidogyne incognita. The nematicidal metabolite isolated from the culture filtrate of JCK-4087 was identified as cyclopiazonic acid (CPA). Because JCK-4087 also produced aflatoxins, six strains of Penicillium commune, which have been reported to be CPA producers, were obtained from the bank and then tested for their CPA productivity. CPA was isolated from the culture filtrate of P. commune KACC 45973. CPA killed the second-stage juveniles of M. incognita, M. hapla, and M. arearia with EC50–3 days 4.50, 18.82, and 60.51 μg mL–1, respectively. CPA also significantly inhibited egg hatch of M. incognita and M. hapla after a total of 28 days of treatment with the concentrations > 25 μg mL–1. The enhancement of CPA production by P. commune KACC 45973 was explored using an optimized medium based on Plackett–Burman design (PBD) and central composite design (CCD). The highest CPA production (381.48 μg mL–1) was obtained from the optimized medium, exhibiting an increase of 7.88 times when compared with that from potato dextrose broth culture. Application of the wettable power-type formulation of the ethyl acetate extract of the culture filtrate of KACC 45973 reduced gall formation and nematode populations in tomato roots and soils under greenhouse conditions. These results suggest that CPA produced by P. commune KACC 45973 can be used as either a biochemical nematicide or a lead molecule for developing chemical nematicides to control root-knot nematodes.
Overlapping Roles of Yeast Transporters Aqr1, Qdr2, and Qdr3 in Amino Acid Excretion and Cross-Feeding of Lactic Acid Bacteria
Authors: Kapetanakis George C. , Gournas Christos , Prévost Martine , Georis Isabelle , André Bruno
Published: November 2021

Microbial species occupying the same ecological niche or codeveloping during a fermentation process can exchange metabolites and mutualistically influence each other’s metabolic states. For instance, yeast can excrete amino acids, thereby cross-feeding lactic acid bacteria unable to grow without an external amino acid supply. The yeast membrane transporters involved in amino acid excretion remain poorly known. Using a yeast mutant overproducing and excreting threonine (Thr) and its precursor homoserine (Hom), we show that excretion of both amino acids involves the Aqr1, Qdr2, and Qdr3 proteins of the Drug H+-Antiporter Family (DHA1) family. We further investigated Aqr1 as a representative of these closely related amino acid exporters. In particular, structural modeling and molecular docking coupled to mutagenesis experiments and excretion assays enabled us to identify residues in the Aqr1 substrate-binding pocket that are crucial for Thr and/or Hom export. We then co-cultivated yeast and Lactobacillus fermentum in an amino-acid-free medium and found a yeast mutant lacking Aqr1, Qdr2, and Qdr3 to display a reduced ability to sustain the growth of this lactic acid bacterium, a phenotype not observed with strains lacking only one of these transporters. This study highlights the importance of yeast DHA1 transporters in amino acid excretion and mutualistic interaction with lactic acid bacteria.
Experimental and Meta-Analytic Validation of RNA Sequencing Signatures for Predicting Status of Microsatellite Instability
Authors: Sorokin Maksim , Rabushko Elizaveta , Efimov Victor , Poddubskaya Elena , Sekacheva Marina , Simonov Alexander , Nikitin Daniil , Drobyshev Aleksey , Suntsova Maria , Buzdin Anton
Published: November 2021

Microsatellite instability (MSI) is an important diagnostic and prognostic cancer biomarker. In colorectal, cervical, ovarian, and gastric cancers, it can guide the prescription of chemotherapy and immunotherapy. In laboratory diagnostics of susceptible tumors, MSI is routinely detected by the size of marker polymerase chain reaction products encompassing frequent microsatellite expansion regions. Alternatively, MSI status is screened indirectly by immunohistochemical interrogation of microsatellite binding proteins. RNA sequencing (RNAseq) profiling is an emerging source of data for a wide spectrum of cancer biomarkers. Recently, three RNAseq-based gene signatures were deduced for establishing MSI status in tumor samples. They had 25, 15, and 14 gene products with only one common gene. However, they were developed and tested on the incomplete literature of The Cancer Genome Atlas (TCGA) sampling and never validated experimentally on independent RNAseq samples. In this study, we, for the first time, systematically validated these three RNAseq MSI signatures on the literature colorectal cancer (CRC) (n = 619), endometrial carcinoma (n = 533), gastric cancer (n = 380), uterine carcinosarcoma (n = 55), and esophageal cancer (n = 83) samples and on the set of experimental CRC RNAseq samples (n = 23) for tumors with known MSI status. We found that all three signatures performed well with area under the curve (AUC) ranges of 0.94–1 for the experimental CRCs and 0.94–1 for the TCGA CRC, esophageal cancer, and uterine carcinosarcoma samples. However, for the TCGA endometrial carcinoma and gastric cancer samples, only two signatures were effective with AUC 0.91–0.97, whereas the third signature showed a significantly lower AUC of 0.69–0.88. Software for calculating these MSI signatures using RNAseq data is included.
miR-15a-3p Protects Against Isoniazid-Induced Liver Injury via Suppressing N-Acetyltransferase 2 Expression
Authors: Li Xinmei , Zhang Heng , Xu Lin , Jin Yuan , Luo Jiao , Li Chuanhai , Zhao Kunming , Zheng Yuxin , Yu Dianke , Zhao Yanjie
Published: November 2021

Isoniazid (INH), an effective first-line drug for tuberculosis treatment, has been reported to be associated with hepatotoxicity for decades, but the underlying mechanisms are poorly understood. N-acetyltransferase 2 (NAT2) is a Phase II enzyme that specifically catalyzes the acetylation of INH, and NAT2 expression/activity play pivotal roles in INH metabolism, drug efficacy, and toxicity. In this study, we systematically investigated the regulatory roles of microRNA (miRNA) in NAT2 expression and INH-induced liver injury via a series of in silico, in vitro, and in vivo analyses. Four mature miRNAs, including hsa-miR-15a-3p, hsa-miR-628-5p, hsa-miR-1262, and hsa-miR-3132, were predicted to target the NAT2 transcript, and a negative correlation was observed between hsa-miR-15a-3p and NAT2 transcripts in liver samples. Further experiments serially revealed that hsa-miR-15a-3p was able to interact with the 3′-untranslated region (UTR) of NAT2 directly, suppressed the endogenous NAT2 expression, and then inhibited INH-induced NAT2 overexpression as well as INH-induced liver injury, both in liver cells and mouse model. In summary, our results identified hsa-miR-15a-3p as a novel epigenetic factor modulating NAT2 expression and as a protective module against INH-induced liver injury, and provided new clues to elucidate the epigenetic regulatory mechanisms concerning drug-induced liver injury (DILI).
Platinum-Induced Peripheral Neuropathy (PIPN): ROS-Related Mechanism, Therapeutic Agents, and Nanosystems
Authors: Hu Xi , Jiang Zhijie , Teng Longyu , Yang Hongyu , Hong Dongsheng , Zheng Dongsheng , Zhao Qingwei
Published: November 2021

Platinum (Pt) drugs (e.g., oxaliplatin, cisplatin) are applied in the clinic worldwide for the treatment of various cancers. However, platinum-induced peripheral neuropathy (PIPN) caused by the accumulation of Pt in the peripheral nervous system limits the clinical application, whose prevention and treatment are still a huge challenge. To date, Pt-induced reactive oxygen species (ROS) generation has been studied as one of the primary mechanisms of PIPN, whose downregulation would be feasible to relieve PIPN. This review will discuss ROS-related PIPN mechanisms including Pt accumulation in the dorsal root ganglia (DRG), ROS generation, and cellular regulation. Based on them, some antioxidant therapeutic drugs will be summarized in detail to alleviate the Pt-induced ROS overproduction. More importantly, we focus on the cutting-edge nanotechnology in view of ROS-related PIPN mechanisms and will discuss the rational fabrication of tailor-made nanosystems for efficiently preventing and treating PIPN. Last, the future prospects and potential breakthroughs of these anti-ROS agents and nanosystems will be briefly discussed.
Lipopolysaccharide, Identified Using an Antibody and by PAS Staining, Is Associated With Corpora amylacea and White Matter Injury in Alzheimer's Disease and Aging Brain
Authors: Zhan Xinhua , Hakoupian Marisa , Jin Lee-Way , Sharp Frank R.
Published: November 2021

Corpora amylacea (CA) increase in number and size with aging. Their origins and functions remain unknown. Previously, we found that Alzheimer's disease (AD) brains have more CA in the periventricular white matter (PVWM) compared to aging controls. In addition, CA is associated with neurodegeneration as indicated by colocalization of degraded myelin basic protein (dMBP) with periodic acid-Schiff (PAS), a CA marker. We also found that bacterial lipopolysaccharide is present in aging brains, with more LPS in AD compared with controls. Periodic acid-Schiff staining is used to identify CA by virtue of their high polysaccharide content. Despite the growing knowledge of CA as a contributor to AD pathology, the molecules that contribute to the polysaccharides in CA are not known. Notably, lipopolysaccharides (LPS) are important cell-surface polysaccharides found in all Gram-negative bacteria. However, it is unknown whether PAS could detect LPS, whether the LPS found in aging brains contribute to the polysaccharide found in CA, and whether LPS associate with myelin injury. In this study, we found that aging brains had a myelin deficit zone (MDZ) adjacent to the ventricles in PVWM. The MDZ contained vesicles, most of which were CA. LPS and dMBP levels were higher in AD than in control brains. LPS was colocalized with dMBP in the vesicles/CA, linking white matter injury with a bacterial pro-inflammatory molecule. The vesicles also contained oxidized fibers, C-reactive protein, NG2, and GALC, markers of oligodendrocyte precursor cells (OPCs) and oligodendrocyte cells (OLs), respectively. The vesicles/CA were surrounded by dense astrocyte processes in control and AD brains. LPS was co-localized with CA by double staining of PAS with LPS in aging brains. The relationship of LPS with PAS staining was confirmed by PAS staining of purified LPS on nitrocellulose membranes. These findings reveal that LPS is one of the polysaccharides found in CA which can be stained with PAS. In addition, vesicles/CA are associated with oxidized and damaged myelin. The LPS in these vesicles/CA may have contributed to this oxidative myelin damage and may have contributed to oxidative stress to OPCs and OLs which could impair the ability to repair damaged myelin in AD and control brains.