bluuebunny/crossref_metadata_2025 huggingface dataset:
Case Report: Bilateral Epiphysiodesis Due to Extreme Tall Stature in a Girl With a De Novo DNMT3A Variant Associated With Tatton-Brown-Rahman Syndrome
Authors: Lennartsson Otto , Lodefalk Maria , Wehtje Henrik , Stattin Eva-Lena , Sävendahl Lars , Nilsson Ola
Published: October 2021

Objective

To present a rare clinical case of a patient with Tatton-Brown-Rahman syndrome and the outcome of tall stature management with bilateral epiphysiodesis surgery at the distal femur and proximal ends of tibia and fibula.

Study Design

Clinical case report.

Results

This is a 20-year-old female with a history of proportional tall stature, developmental psychomotor and language delay with autism spectrum behavior and distinctive facial features. At 12 years and 2 months of age she was in early puberty and 172.5 cm tall (+ 2.8 SDS) and growing approximately 2 SDS above midparental target height of 173 cm (+ 0.9 SDS). A bone age assessment predicted an adult height of 187.1 cm (+3.4 SDS). To prevent extreme tall stature, bilateral epiphysiodesis surgery was performed at the distal femur and proximal ends of tibia and fibula at the age of 12 years and 9 months. After the surgery her height increased by 12.6 cm to 187.4 cm of which approximately 10.9 cm occurred in the spine whereas leg length increased by only 1.7 cm resulting in a modest increase of sitting height index from 50% (-1 SDS) to 53% (+ 0.5 SDS). Genetic evaluation for tall stature and intellectual disability identified a de novo nonsense variant in the DNMT3A gene previously associated with Tatton-Brown-Rahman syndrome.

Conclusion

Tatton-Brown-Rahman syndrome should be considered in children with extreme tall stature and intellectual disability. Percutaneous epiphysiodesis surgery to mitigate extreme tall stature may be considered.
Metoidioplasty: Surgical Options and Outcomes in 813 Cases
Authors: Bordas Noemi , Stojanovic Borko , Bizic Marta , Szanto Arpad , Djordjevic Miroslav L.
Published: October 2021

Introduction

Metoidioplasty is a variant of phalloplasty for transmen that includes the creation of the neophallus from a hormonally enlarged clitoris, urethral lengthening and scrotoplasty. The procedure results in male appearance of genitalia, voiding in standing position and preserved sexual arousal, but without possibility for penetrative intercourse. We evaluated outcomes of metoidioplasty at our center, based on latest surgical refinements.

Methods

During the period of 14 years (from February 2006 to April 2020), 813 transmen with mean age of 24.4 years and mean body mass index of 24.6, underwent one stage metoidioplasty. Hysterectomy was simultaneously performed in 156, and mastectomy in 58 cases. Hysterectomy, mastectomy and metoidioplasty were done as a one-stage procedure in 46 transmen. Patients are divided in 5 groups, depending on the type of urethroplasty. Postoperative questionnaires were used to evaluate cosmetic and functional outcomes, as well as patients’ satisfaction.

Results

Follow-up ranged from 16 to 180 months (mean 94 months). Mean surgery time was 170 minutes and mean hospital stay was 3 days. Length of the neophallus ranged from 4.8 cm to 10.2 cm (mean 5.6 cm). Urethroplasty was complication-free in 89.5% of cases, and ranged between 81% to 90.3% in different groups. Urethral fistula and stricture occured in 8.85% and 1.70% of cases, respectively. Other complications included testicular implant rejection in 2%, testicular displacement in 3.20% and vaginal remnant in 9.60% of cases. From 655 patients who answered the questionnaire, 79% were totally satisfied and 20% mainly satisfied with the result of surgery. All patients reported voiding in standing position and good sexual arousal of the neophallus, without possibility for penetrative intercourse due to small size of the neophallus.

Conclusion

Metoidioplasty has good cosmetic and functional outcomes, with low complication rate and high level of patients’ satisfaction. In transmen who request total phalloplasty after metoidioplasty, all available phalloplasty techniques are feasable.
Long-Term Health Outcomes of Korean Adults With Classic Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency
Authors: Lim Seung Gyun , Lee Young Ah , Jang Han Na , Kong Sung Hye , Ahn Chang Ho , Kim Sang Wan , Shin Choong Ho , Kim Jung Hee
Published: October 2021

There is a lack of studies regarding the long-term outcomes of Asian adults with classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency. We hypothesized that adults with CAH are at higher metabolic risk than their age-, and sex-matched controls. We further investigated the long-term health outcome-related factors in adults with CAH. We compared metabolic risk between adults with CAH (71 men, 93 women) and age-, and sex-matched controls (190 men, 261 women) from the Korean National Health and Nutrition Examination Survey data. The presence of obesity, testicular adrenal rest tumors (TARTs), and menstrual irregularity was assessed. Hormone status and treatment regimens were compared according to the presence of adverse outcomes. The median age was 27.0 y and 28.0 y for men and women, respectively. Adults with CAH had a higher waist circumference (88.0 vs. 82.3 cm in men, and 83.5 vs. 72.3 cm in women), and blood pressure (125.0 vs. 113.0 mmHg in men, and 120.0 vs. 104.0 mmHg in women) than age- and sex-matched controls (P<0.05 for all). The 2.7-fold increased risk for hypertension (men) and 2.0-fold increased risk for obesity (women) was significant in patients with CAH (P<0.05 for both). Obese adults with CAH showed significantly higher adrenal limb thicknesses (men) and 17-hydroxyprogesterone and dehydroepiandrosterone sulfate levels (women) (P<0.05 for both). TARTs occurred in 58.1% of men and did not differ by hormone or treatment regimen. Irregular menstruation was observed in 57.1% of women, with higher dehydroepiandrosterone sulfate levels in those with irregular periods. Adults with CAH had a higher metabolic risk than the general population. Poor disease control may increase their risk of metabolic morbidity and menstrual irregularity.
Genetic Analysis of 28 Chinese Families With Tyrosinase-Positive Oculocutaneous Albinism
Authors: Ma Linya , Zhu Jianjian , Wang Jing , Huang Yazhou , Zhang Jibo , Wang Chao , Zhou Yuan , Peng Dan
Published: October 2021

Background

Tyrosinase-positive oculocutaneous albinism (OCA, type II, OCA2) is an autosomal recessive genetic disease in which the biosynthesis of melanin decreases in the skin, hair, and eyes. OCA2 disease is caused by mutations inOCA2gene. The gene product plays a role in regulating the pH of melanosomes. Up to now, hundreds ofOCA2mutations have been reported and novel variants are still being discovered.

Methods

In this study, we reviewed the records of OCA2 patients who had conducted albinism genetic testing, and then analyzed the clinical and genetic information of 28 OCA2 patients who had been genetically diagnosed by using Sanger sequencing and next-generation sequencing.

Results

In this study, we reported 31 variants screened from 28 Chinese OCA2 families, and characterized the detailed molecular and clinical presentations. There were 12 novel variants among all detected variants, including 3 missense variants (p.G393V, p.T482A, and p.R720P), 4 frameshift variants (p.R53Gfs∗49, p.N279Kfs∗17, p.I469Lfs∗4, p.I655Nfs∗12), 2 splicing variants (c.1637-2A > G, c.1951 + 1G > C), 2 stopgain variants (p.L278X, p.W652X) and 1 insertion variants (p.P315LinsT). One potential cluster of missense variants was implicated indicating the important roles of the underlying domains in OCA2 pathogenesis.

Conclusion

Our results were beneficial for diagnosis and precision clinical management forOCA2-related disorder, and this study expanded the mutation spectrum of oculocutaneous albinism.
Molecular Cytogenetics in the Era of Chromosomics and Cytogenomic Approaches
Authors: Liehr Thomas
Published: October 2021

Here the role of molecular cytogenetics in the context of yet available all other cytogenomic approaches is discussed. A short introduction how cytogenetics and molecular cytogenetics were established is followed by technical aspects of fluorescence in situ hybridization (FISH). The latter contains the methodology itself, the types of probe- and target-DNA, as well as probe sets. The main part deals with examples of modern FISH-applications, highlighting unique possibilities of the approach, like the possibility to study individual cells and even individual chromosomes. Different variants of FISH can be used to retrieve information on genomes from (almost) base pair to whole genomic level, as besides only second and third generation sequencing approaches can do. Here especially highlighted variations of FISH are molecular combing, chromosome orientation-FISH (CO-FISH), telomere-FISH, parental origin determination FISH (POD-FISH), FISH to resolve the nuclear architecture, multicolor-FISH (mFISH) approaches, among other applied in chromoanagenesis studies, Comet-FISH, and CRISPR-mediated FISH-applications. Overall, molecular cytogenetics is far from being outdated and actively involved in up-to-date diagnostics and research.
The Causal Effects of Insomnia on Bipolar Disorder, Depression, and Schizophrenia: A Two-Sample Mendelian Randomization Study
Authors: Huang Peng , Zou Yixin , Zhang Xingyu , Ye Xiangyu , Wang Yidi , Yu Rongbin , Yang Sheng
Published: October 2021

Psychiatric disorder, including bipolar disorder (BD), major depression (MDD), and schizophrenia (SCZ), affects millions of persons around the world. Understanding the disease causal mechanism underlying the three diseases and identifying the modifiable risk factors for them hold the key for the development of effective preventative and treatment strategies. We used a two-sample Mendelian randomization method to assess the causal effect of insomnia on the risk of BD, MDD, and SCZ in a European population. We collected one dataset of insomnia, three of BD, one of MDD, and three of SCZ and performed a meta-analysis for each trait, further verifying the analysis through extensive complementarity and sensitivity analysis. Among the three psychiatric disorders, we found that only insomnia is causally associated with MDD and that higher insomnia increases the risk of MDD. Specifically, the odds ratio of MDD increase of insomnia is estimated to be 1.408 [95% confidence interval (CI): 1.210–1.640, p = 1.03E-05] in the European population. The identified causal relationship between insomnia and MDD is robust with respect to the choice of statistical methods and is validated through extensive sensitivity analyses that guard against various model assumption violations. Our results provide new evidence to support the causal effect of insomnia on MDD and pave ways for reducing the psychiatric disorder burden.
Podoplanin Drives Motility of Active Macrophage via Regulating Filamin C During Helicobacter pylori Infection
Authors: Cheok Yi Ying , Tan Grace Min Yi , Fernandez Keith Conrad , Chan Yee Teng , Lee Chalystha Yie Qin , Cheong Heng Choon , Looi Chung Yeng , Vadivelu Jamuna , Abdullah Suhailah , Wong Won Fen
Published: October 2021

Podoplanin (Pdpn) is a mucin-type transmembrane protein that has been implicated in multiple physiological settings including lymphangiogenesis, platelet aggregation, and cancer metastasis. Here, we reported an absence of Pdpn transcript expression in the resting mouse monocytic macrophages, RAW264.7 cells; intriguingly, a substantial upregulation of Pdpn was observed in activated macrophages following Helicobacter pylori or lipopolysaccharide stimulation. Pdpn-knockout macrophages demonstrated intact phagocytic and intracellular bactericidal activities comparable to wild type but exhibited impaired migration due to attenuated filopodia formation. In contrast, an ectopic expression of Pdpn augmented filopodia protrusion in activated macrophages. NanoString analysis uncovered a close dependency of Filamin C gene on the presence of Pdpn, highlighting an involvement of Filamin C in modulation of actin polymerization activity, which controls cell filopodia formation and migration. In addition, interleukin-1β production was significantly declined in the absence of Pdpn, suggesting a role of Pdpn in orchestrating inflammation during H. pylori infection besides cellular migration. Together, our findings unravel the Pdpn network that modulates movement of active macrophages.
TNFSF13 Is a Novel Onco-Inflammatory Marker and Correlates With Immune Infiltration in Gliomas
Authors: Chen Rui , Wang Xinxing , Dai Ziyu , Wang Zeyu , Wu Wantao , Hu Zhengang , Zhang Xun , Liu Zhixiong , Zhang Hao , Cheng Quan
Published: October 2021

Existing therapeutic strategies for gliomas are restricted; hence, exploration for novel diagnostic indicator and treatment is essential. Here, we performed bioinformatic analyses for TNFSF13 (also known as APRIL), a proliferation-inducing ligand of the tumor necrosis factor (TNF) superfamily, aiming to assess its potential for predicting glioma patient’s prognosis and targeted therapy. TNFSF13 expression was upregulated in the increase of tumor grades based on Xiangya cohort. In high TNFSF13 gliomas, somatic mutation was proved to correlate with amplification of EGFR and deletion of CDKN2A; while mutation of IDH1 was more frequently observed in low TNFSF13 group. We also confirmed the positive correlation between TNFSF13 and infiltrating immune and stromal cells in glioma microenvironment. Further, TNFSF13 was found to be involved in immunosuppression via diverse immunoregulation pathways and was associated with other immune checkpoints and inflammation. Single-cell sequencing revealed an abundant expression of TNFSF13 in neoplastic cells and M2 macrophages, which TNFSF13 might potentially regulate the cell communication via IL-8, C3, and CD44. Lastly, TNFSF13 mediated the activities of transcription factors including FOXO3, MEIS2, and IRF8. Our analyses demonstrated the relevance between TNFSF13 and glioma progress and indicated the potential of TNFSF13 as a novel diagnostic onco-inflammatory biomarker and immunotherapy target of gliomas.
Non-Stimulatory pMHC Enhance CD8 T Cell Effector Functions by Recruiting Coreceptor-Bound Lck
Authors: Zhao Xiang , Wu Liang-Zhe , Ng Esther K. Y. , Leow Kerisa W. S. , Wei Qianru , Gascoigne Nicholas R. J. , Brzostek Joanna
Published: October 2021

Under physiological conditions, CD8+ T cells need to recognize low numbers of antigenic pMHC class I complexes in the presence of a surplus of non-stimulatory, self pMHC class I on the surface of the APC. Non-stimulatory pMHC have been shown to enhance CD8+ T cell responses to low amounts of antigenic pMHC, in a phenomenon called co-agonism, but the physiological significance and molecular mechanism of this phenomenon are still poorly understood. Our data show that co-agonist pMHC class I complexes recruit CD8-bound Lck to the immune synapse to modulate CD8+ T cell signaling pathways, resulting in enhanced CD8+ T cell effector functions and proliferation, both in vitro and in vivo. Moreover, co-agonism can boost T cell proliferation through an extrinsic mechanism, with co-agonism primed CD8+ T cells enhancing Akt pathway activation and proliferation in neighboring CD8+ T cells primed with low amounts of antigen.
Influenza Vaccination Is Associated With Lower Incidental Asthma Risk in Patients With Atopic Dermatitis: A Nationwide Cohort Study
Authors: Li Kun Hong , Leong Pui-Ying , Tseng Chung-Fang , Wang Yu Hsun , Wei James Cheng-Chung
Published: October 2021

Background

Atopic march refers to the natural history of atopic dermatitis (AD) in infancy followed by subsequent allergic rhinitis and asthma in later life. Respiratory viruses interact with allergic sensitization to promote recurrent wheezing and the development of asthma. We aimed to evaluate whether influenza vaccination reduces asthma risk in people with AD.

Methods

This cohort study was conducted retrospectively from 2000 to 2013 by the National Health Insurance Research Database (NHIRD). Patients with newly diagnosed AD (International Classification of Diseases, Ninth Revision, Clinical Modification code 691) were enrolled as the AD cohort. We matched each vaccinated patient with one non-vaccinated patient according to age and sex. We observed each participant until their first asthma event, or the end of the study on December 31, 2013, whichever came first.

Results

Our analyses included 4,414 people with a mean age of 53 years. Of these, 43.8 were male. The incidence density of asthma was 12.6 per 1,000 person-years for vaccinated patients, and 15.1 per 1000 person-years for non-vaccinated patients. The adjusted hazard ratio (aHR) of asthma in the vaccinated cohort relative to the non-vaccinated cohort was 0.69 (95% CI = 0.55–0.87). Vaccinated patients had a lower cumulative incidence of asthma than unvaccinated patients. Vaccinated participants in all age and sex groups trended toward a lower risk of asthma. People will reduce more asthma risk when taking shots every year.

Conclusion

Influenza vaccination was associated with lower asthma risk in patients with AD.
NLRP3 Inflammasome: Checkpoint Connecting Innate and Adaptive Immunity in Autoimmune Diseases
Authors: Zhang Yiwen , Yang Wenlin , Li Wangen , Zhao Yunjuan
Published: October 2021

Autoimmune diseases are a broad spectrum of human diseases that are characterized by the breakdown of immune tolerance and the production of autoantibodies. Recently, dysfunction of innate and adaptive immunity is considered to be a key step in the initiation and maintenance of autoimmune diseases. NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome is a multimeric protein complex, which can detect exogenous pathogen irritants and endogenous danger signals. The main function of NLRP3 inflammasome is to promote secretion of interleukin (IL)-1β and IL-18, and pyroptosis mediated by caspase-1. Served as a checkpoint in innate and adaptive immunity, aberrant activation and regulation of NLRP3 inflammasome plays an important role in the pathogenesis of autoimmune diseases. This paper reviewed the roles of NLRP3 inflammasome in autoimmune diseases, which shows NLRP3 inflammasome may be a potential target for autoimmune diseases deserved further study.
Early Pro-Inflammatory Signal and T-Cell Activation Associate With Vaccine-Induced Anti-Vaccinia Protective Neutralizing Antibodies
Authors: Hou Jue , Wang Shuhui , Li Dan , Carpp Lindsay N. , Zhang Tong , Liu Ying , Jia Manxue , Peng Hong , Liu Chang , Wu Hao , Huang Yunda , Shao Yiming
Published: October 2021

Both vaccine “take” and neutralizing antibody (nAb) titer are historical correlates for vaccine-induced protection from smallpox. We analyzed a subset of samples from a phase 2a trial of three DNA/HIV-1 primes and a recombinant Tiantan vaccinia virus-vectored (rTV)/HIV-1 booster and found that a proportion of participants showed no anti-vaccinia nAb response to the rTV/HIV-1 booster, despite successful vaccine “take.” Using a rich transcriptomic and vaccinia-specific immunological dataset with fine kinetic sampling, we investigated the molecular mechanisms underlying nAb response. Blood transcription module analysis revealed the downregulation of the activator protein 1 (AP-1) pathway in responders, but not in non-responders, and the upregulation of T-cell activation in responders. Furthermore, transcriptional factor network reconstruction revealed the upregulation of AP-1 core genes at hour 4 and day 1 post-rTV/HIV-1 vaccination, followed by a downregulation from day 3 until day 28 in responders. In contrast, AP-1 core and pro-inflammatory genes were upregulated on day 7 in non-responders. We speculate that persistent pro-inflammatory signaling early post-rTV/HIV-1 vaccination inhibits the nAb response.
Siglec-8 Signals Through a Non-Canonical Pathway to Cause Human Eosinophil Death In Vitro
Authors: Carroll Daniela J. , Cao Yun , Bochner Bruce S. , O’Sullivan Jeremy A.
Published: October 2021

Sialic acid-binding immunoglobulin-like lectin (Siglec)-8 is a glycan-binding receptor bearing immunoreceptor tyrosine-based inhibitory and switch motifs (ITIM and ITSM, respectively) that is selectively expressed on eosinophils, mast cells, and, to a lesser extent, basophils. Previous work has shown that engagement of Siglec-8 on IL-5–primed eosinophils causes cell deathviaCD11b/CD18 integrin–mediated adhesion and NADPH oxidase activity and identified signaling molecules linking adhesion, reactive oxygen species (ROS) production, and cell death. However, the proximal signaling cascade activated directly by Siglec-8 engagement has remained elusive. Most members of the Siglec family possess similar cytoplasmic signaling motifs and recruit the protein tyrosine phosphatases SHP-1/2, consistent with ITIM-mediated signaling, to dampen cellular activation. However, the dependence of Siglec-8 function in eosinophils on these phosphatases has not been studied. Using Siglec-8 antibody engagement and pharmacological inhibition in conjunction with assays to measure cell-surface upregulation and conformational activation of CD11b integrin, ROS production, and cell death, we sought to identify molecules involved in Siglec-8 signaling and determine the stage of the process in which each molecule plays a role. We demonstrate here that the enzymatic activities of Src family kinases (SFKs), Syk, SHIP1, PAK1, MEK1, ERK1/2, PLC, PKC, acid sphingomyelinase/ceramidase, and Btk are all necessary for Siglec-8–induced eosinophil cell death, with no apparent role for SHP-1/2, SHIP2, or c-Raf. While most of these signaling molecules are necessary for Siglec-8–induced upregulation of CD11b integrin at the eosinophil cell surface, Btk is phosphorylated and activated later in the signaling cascade and is instead necessary for CD11b activation. In contrast, SFKs and ERK1/2 are phosphorylated far earlier in the process, consistent with their role in augmenting cell-surface levels of CD11b. In addition, pretreatment of eosinophils with latrunculin B or jasplakinolide revealed that actin filament disassembly is necessary and sufficient for surface CD11b integrin upregulation and that actin polymerization is necessary for downstream ROS production. These results show that Siglec-8 signals through an unanticipated set of signaling molecules in IL-5–primed eosinophils to induce cell death and challenges the expectation that ITIM-bearing Siglecs signal through inhibitory pathways involving protein tyrosine phosphatases to achieve their downstream functions.
Transport Stress Induces Skin Innate Immunity Response in Hybrid Yellow Catfish (Tachysurus fulvidraco♀ × P. vachellii♂) Through TLR/NLR Signaling Pathways and Regulation of Mucus Secretion
Authors: Zheng Tao , Song Zhuo , Qiang Jun , Tao Yifan , Zhu Haojun , Ma Junlei , Xu Pao
Published: October 2021

The transport of live fish is a necessary step for commercial production. The skin of teleost fish is the first non-specific immune barrier against exogenous stimuli, and it plays an important protective role under transport stress. Thus, the aim of this study was to explore the skin responses to transport stress in hybrid yellow catfish (Tachysurus fulvidraco♀ × Pseudobagrus vachellii♂) through transcriptome and biochemical analyses. Water samples were collected during a simulated transport treatment. Biochemical indexes and/or gene expression in blood, skin, and mucus in fish in control groups and transport-stress groups (0 h, 2 h, 4 h, 8 h, 16 h) were assayed. The levels of total ammonia–nitrogen and nitrite–nitrogen in the water increased with increasing transport time. Comparison of skin transcriptomes between the control group and the group subjected to 16 h of transport revealed 1547 differentially expressed genes (868 up-regulated and 679 down-regulated). The results of the transcriptome analysis were validated by analyses of the expression levels of selected genes by qRT-PCR. The results indicated that the toll-like receptors and nod-like receptors signaling pathways mediate the skin’s immune response to transport stress: tlr9, mfn2, and ikbke were significantly up-regulated and nfkbia and map3k7cl were significantly down-regulated under transport stress. With increasing transport time, lysozyme activity and the immunoglobulin M content in skin mucus first increased and then decreased. The number of mucous cells peaked at 8 h of transport stress, and then decreased. The mucus cells changed from types II and IV to types I, II, III, and IV. The amounts of red and white blood cells and the levels of hemoglobin and hematocrit first increased and then decreased during 16 h of transport stress. Together, the results showed that the skin responds to transport stress by activating the immune signaling pathway and regulating mucus secretion. These findings have important biological significance for selecting strains that tolerate transport, as well as economic significance for optimizing the transport conditions for scaleless fish.
Children and Adults in a Household Cohort Study Have Robust Longitudinal Immune Responses Following SARS-CoV-2 Infection or Exposure
Authors: Neeland Melanie R. , Bannister Samantha , Clifford Vanessa , Nguyen Jill , Dohle Kate , Overmars Isabella , Toh Zheng Quan , Anderson Jeremy , Donato Celeste M. , Sarkar Sohinee , Do Lien Anh Ha , McCafferty Conor , Licciardi Paul V. , Ignjatovic Vera , Monagle Paul , Bines Julie E. , Mulholland Kim , Curtis Nigel , McNab Sarah , Steer Andrew C. , Burgner David P. , Saffery Richard , Tosif Shidan , Crawford Nigel W.
Published: October 2021

Children have reduced severity of COVID-19 compared to adults and typically have mild or asymptomatic disease. The immunological mechanisms underlying these age-related differences in clinical outcomes remain unexplained. Here, we quantify 23 immune cell populations in 141 samples from children and adults with mild COVID-19 and their PCR-negative close household contacts at acute and convalescent time points. Children with COVID-19 displayed marked reductions in myeloid cells during infection, most prominent in children under the age of five. Recovery from infection in both children and adults was characterised by the generation of CD8 TCM and CD4 TCM up to 9 weeks post infection. SARS-CoV-2-exposed close contacts also had immunological changes over time despite no evidence of confirmed SARS-CoV-2 infection on PCR testing. This included an increase in low-density neutrophils during convalescence in both exposed children and adults, as well as increases in CD8 TCM and CD4 TCM in exposed adults. In comparison to children with other common respiratory viral infections, those with COVID-19 had a greater change in innate and T cell-mediated immune responses over time. These findings provide new mechanistic insights into the immune response during and after recovery from COVID-19 in both children and adults.
Identification of Cell Surface Molecules That Determine the Macrophage Activation Threshold Associated With an Early Stage of Malignant Transformation
Authors: Jacqueline Camille , Dracz Matthew , Boothman Sarah , Minden Jonathan S. , Gottschalk Rachel A. , Finn Olivera J.
Published: October 2021

The ability of immune cells to sense changes associated with malignant transformation as early as possible is likely to be important for the successful outcome of cancer immunosurveillance. In this process, the immune system faces a trade-off between elimination of cells harboring premalignant or malignant changes, and autoimmune pathologies. We hypothesized that the immune system has therefore evolved a threshold for the stage of transformation from normal to fully malignant cells that first provides a threat (danger) signal requiring a response. We co-cultured human macrophages with a unique set of genetically related human cell lines that recapitulate successive stages in breast cancer development: MCF10A (immortalized, normal); MCFNeoT (benign hyperplasia); MCFT1 (atypical hyperplasia); MCFCA1 (invasive cancer). Using cytokines-based assays, we found that macrophages were inert towards MCF10A and MCFNeoT but were strongly activated by MCFT1 and MCFCA1 to produce inflammatory cytokines, placing the threshold for recognition between two premalignant stages, the earlier stage MCFNeoT and the more advanced MCFT1. The cytokine activation threshold paralleled the threshold for enhanced phagocytosis. Using proteomic and transcriptomic approaches, we identified surface molecules, some of which are well-known tumor-associated antigens, that were absent or expressed at low levels in MCF10A and MCFNeoT but turned on or over-expressed in MCFT1 and MCFCA1. Adding antibodies specific for two of these molecules, Annexin-A1 and CEACAM1, inhibited macrophage activation, supporting their role as cancer “danger signals” recognized by macrophages.
NLRC5 Deficiency Deregulates Hepatic Inflammatory Response but Does Not Aggravate Carbon Tetrachloride-Induced Liver Fibrosis
Authors: Quenum Akouavi Julite I. , Shukla Akhil , Rexhepi Fjolla , Cloutier Maryse , Ghosh Amit , Kufer Thomas A. , Ramanathan Sheela , Ilangumaran Subburaj
Published: October 2021

The nucleotide-binding leucine-rich repeat-containing receptor (NLR) family protein-5 (NLRC5) controls NF-κB activation and production of inflammatory cytokines in certain cell types. NLRC5 is considered a potential regulator of hepatic fibrogenic response due to its ability to inhibit hepatic stellate activation in vitro. To test whether NLRC5 is critical to control liver fibrosis, we treated wildtype and NLRC5-deficient mice with carbon tetrachloride (CCl4) and assessed pathological changes in the liver. Serum alanine transaminase levels and histopathology examination of liver sections revealed that NLRC5 deficiency did not exacerbate CCl4-induced liver damage or inflammatory cell infiltration. Sirius red staining of collagen fibers and hydroxyproline content showed comparable levels of liver fibrosis in CCl4-treated NLRC5-deficient and control mice. Myofibroblast differentiation and induction of collagen genes were similarly increased in both groups. Strikingly, the fibrotic livers of NLRC5-deficient mice showed reduced expression of matrix metalloproteinase-3 (Mmp3) and tissue inhibitor of MMPs-1 (Timp1) but not Mmp2 or Timp2. Fibrotic livers of NLRC5-deficient mice had increased expression of TNF but similar induction of TGFβ compared to wildtype mice. CCl4-treated control and NLRC5-deficient mice displayed similar upregulation of Cx3cr1, a monocyte chemoattractant receptor gene, and the Cd68 macrophage marker. However, the fibrotic livers of NLRC5-deficient mice showed increased expression of F4/80 (Adgre1), a marker of tissue-resident macrophages. NLRC5-deficient livers showed increased phosphorylation of the NF-κB subunit p65 that remained elevated following fibrosis induction. Taken together, NLRC5 deficiency deregulates hepatic inflammatory response following chemical injury but does not significantly aggravate the fibrogenic response, showing that NLRC5 is not a critical regulator of liver fibrosis pathogenesis.
Effects of Neutrophil Extracellular Traps in Patients With Septic Coagulopathy and Their Interaction With Autophagy
Authors: Mao Jia-Yu , Zhang Jia-Hui , Cheng Wei , Chen Jian-Wei , Cui Na
Published: October 2021

Introduction

Neutrophil extracellular traps (NETs) act as a critical trigger of inflammation and coagulation. We hypothesized that NETs are associated with septic hypercoagulability.

Materials and Methods

In total, 82 patients admitted with sepsis in the Department of Critical Care Medicine of Peking Union Medical College Hospital were enrolled between February 2017 and April 2018. Clinical and hematological parameters and thrombotic or hemorrhagic events were recorded. Blood samples were obtained to assess biomarkers of NET formation, including neutrophil elastase 2 (ELA2) and citrullinated histone H3, and endothelial-derived biomarker syndecan-1. Autophagy levels and their regulation pathway were also examined to explore their interaction with NETs.

Result

Sepsis patients with disseminated intravascular coagulation (DIC) showed significantly higher levels of NET formation [ELA2, 1,247 (86–625) vs. 2,039 (1,544–2,534), p < 0.0001; H3, 140 (47–233) vs. 307 (199–415), p < 0.0001]. NET formation was independently associated with DIC risk [ELA2, OR 1.0028, 95% CI, 1.0010–1.0045; H3, OR 1.0104, 95% CI, 1.0032–1.0176] and mortality [ELA2, HR 1.0014, 95% CI, 1.0004–1.0024; H3, HR 1.0056, 95% CI, 1.0008–1.0115]. The area under the curve value for ELA2 in predicting DIC occurrence was 0.902 (95% CI, 0.816–0.957), and that of H3 was 0.870 (95% CI, 0.778–0.934). Furthermore, biomarkers of NET formation, endothelial cells, and autophagy exhibited a significant correlation [ELA2 and Syn (r = 0.5985, p < 0.0001), LC3B (r = −0.4224, p < 0.0001); H3 and Syn (r = 0.6383, p < 0.0001), LC3B (r = −0.3005, p = 0.0061)].

Conclusion

Increased NET formation is significantly associated with sepsis-induced DIC incidence and mortality in sepsis patients, revealing a significant relationship with the autophagy pathway.

Clinical Trial Registration

chictr.org.cn, identifier ChiCTR-ROC-17010750.
Tilapia Lake Virus-Induced Neuroinflammation in Zebrafish: Microglia Activation and Sickness Behavior
Authors: Mojzesz Miriam , Widziolek Magdalena , Adamek Mikolaj , Orzechowska Urszula , Podlasz Piotr , Prajsnar Tomasz K. , Pooranachandran Niedharsan , Pecio Anna , Michalik Anna , Surachetpong Win , Chadzinska Magdalena , Rakus Krzysztof
Published: October 2021

In mammals, the relationship between the immune system and behavior is widely studied. In fish, however, the knowledge concerning the brain immune response and behavioral changes during brain viral infection is very limited. To further investigate this subject, we used the model of tilapia lake virus (TiLV) infection of zebrafish (Danio rerio), which was previously developed in our laboratory. We demonstrated that TiLV persists in the brain of adult zebrafish for at least 90 days, even when the virus is not detectable in other peripheral organs. The virions were found in the whole brain. During TiLV infection, zebrafish displayed a clear sickness behavior: decreased locomotor activity, reduced food intake, and primarily localizes near the bottom zone of aquaria. Moreover, during swimming, individual fish exhibited also unusual spiral movement patterns. Gene expression study revealed that TiLV induces in the brain of adult fish strong antiviral and inflammatory response and upregulates expression of genes encoding microglia/macrophage markers. Finally, using zebrafish larvae, we showed that TiLV infection induces histopathological abnormalities in the brain and causes activation of the microglia which is manifested by changes in cell shape from a resting ramified state in mock-infected to a highly ameboid active state in TiLV-infected larvae. This is the first study presenting a comprehensive analysis of the brain immune response associated with microglia activation and subsequent sickness behavior during systemic viral infection in zebrafish.
Immunogenomic Analyses of the Prognostic Predictive Model for Patients With Renal Cancer
Authors: Feng Tao , Zhao Jiahui , Wei Dechao , Guo Pengju , Yang Xiaobing , Li Qiankun , Fang Zhou , Wei Ziheng , Li Mingchuan , Jiang Yongguang , Luo Yong
Published: October 2021

Background

Renal cell carcinoma (RCC) is associated with poor prognostic outcomes. The current stratifying system does not predict prognostic outcomes and therapeutic benefits precisely for RCC patients. Here, we aim to construct an immune prognostic predictive model to assist clinician to predict RCC prognosis.

Methods

Herein, an immune prognostic signature was developed, and its predictive ability was confirmed in the kidney renal clear cell carcinoma (KIRC) cohorts based on The Cancer Genome Atlas (TCGA) dataset. Several immunogenomic analyses were conducted to investigate the correlations between immune risk scores and immune cell infiltrations, immune checkpoints, cancer genotypes, tumor mutational burden, and responses to chemotherapy and immunotherapy.

Results

The immune prognostic signature contained 14 immune-associated genes and was found to be an independent prognostic factor for KIRC. Furthermore, the immune risk score was established as a novel marker for predicting the overall survival outcomes for RCC. The risk score was correlated with some significant immunophenotypic factors, including T cell infiltration, antitumor immunity, antitumor response, oncogenic pathways, and immunotherapeutic and chemotherapeutic response.

Conclusions

The immune prognostic, predictive model can be effectively and efficiently used in the prediction of survival outcomes and immunotherapeutic responses of RCC patients.
Cytochrome P450 26A1 Modulates the Polarization of Uterine Macrophages During the Peri-Implantation Period
Authors: Ji Wen-Heng , Li Dan-Dan , Wei Dan-Ping , Gu Ai-Qin , Yang Ying , Peng Jing-Pian
Published: October 2021

Uterine M1/M2 macrophages activation states undergo dynamic changes throughout pregnancy, and inappropriate macrophages polarization can cause adverse pregnancy outcomes, especially during the peri-implantation period. Our previous studies have confirmed that Cytochrome P450 26A1 (CYP26A1) can affect embryo implantation by regulating uterine NK cells and DCs. The aim of this study was to investigate whether CYP26A1 regulates the polarization of uterine macrophages in early pregnancy. Here, we observed that Cyp26a1 was significantly upregulated in M1 as compared with M2 of uterine macrophages, Raw264.7 and iBMDM. Knockdown of CYP26A1 in mice uterine significantly decreased the number of embryo implantation sites and the proportion of CD45+F4/80+CD206− M1-like uterine macrophages. Primary uterine macrophages treated with anti-CYP26A1 antibody expressed significantly lower levels of M1 markers Nos2, Il1b, Il6 and Tnf-a. In CYP26A1 knockout Raw264.7 cells, the protein levels of M1 markers TNF-α, IL-6 and CD86 were significantly decreased as compared with the wild type cells. Moreover, CYP26A1 deficiency decreased the ability to produce nitric oxide and increased the phagocytosis capacity of Raw264.7 cells under M1 stimulation state. The re-introduction of CYP26A1 partially reversed the polarization levels of M1 in CYP26A1 knockout Raw264.7 cells. CYP26A1 may regulate the polarization of uterine macrophages to M1 through Stap1 and Slc7a2. In summary, these results indicate that CYP26A1 plays a significant role in macrophage polarization, and knockdown of CYP26A1 can cause insufficient M1 polarization during the peri-implantation period, which has adverse effects on blastocyst implantation.
ADV-Based Investigation on Bed Level Changes Over a Meso-Macro Tidal Beach
Authors: Pang Wenhong , Zhou Xiaoyan , Dai Zhijun , Li Shushi , Huang Hu , Lei Yaping
Published: October 2021

Beach intra-tidal bed level changes are of significance to coastal protection amid global climate changes. However, due to the limitation of instruments and the disturbance induced by wave motions superimposed on water levels, it was difficult to detect the high-frequency oscillation of the submerged beach bed level. In this study, an observation, lasting for 12 days and covering the middle tide to the following spring tide, was conducted on a meso-macro tidal beach, Yintan Beach, to simultaneously detect the characteristics and influence mechanism of bed level changes at intra-tidal and tidal cycle scales. The collected data included water depth, suspended sediment concentration (SSC), waves, high-frequency three-dimensional (3-D) velocity, and the distance of the seabed to the acoustic Doppler velocimeter (ADV) probe, which were measured by an optical backscatter sensor, two Tide & Wave Recorder-2050s, and an ADV, respectively. The results showed that the tidal cycle-averaged bed level decreased by 58.8 mm, increased by 12.6 mm, and increased by 28.9 mm during neap, middle, and spring tides in succession, respectively, compared with the preceding tidal regimes. The net erosion mainly resulted from large incident wave heights and the consequent strong offshore-directed sediment transport induced by undertows. Moreover, the variations in the bed level were more prominent during a neap to middle tides than during middle to spring tides, which were jointly caused by the wave-breaking probability regulated by water depth and the relative residence times of shoaling wave, breaker, and surf zones that were determined by relative tidal range. In terms of the intra-tidal bed level, it displayed an intra-tidal tendency of increase during floods and decrease during ebb tides, i.e., the intra-tidal bed level changes were controlled by water depth, which modulated the effects of waves on sediment resuspension and vertical sediment exchange. To be specific, waves and SSC were responsible for the intra-tidal bed level changes under low-energy wave conditions, while mean current and bedform exerted important influences on the variations of the intra-tidal bed level under moderate wave conditions, which broke the foregoing interrelation between bed level, waves, and SSC. This study, therefore, emphasizes the usage of ADV measurement to investigate bed level changes in sandy coasts.
Ice-Associated Amphipods in a Pan-Arctic Scenario of Declining Sea Ice
Authors: Hop Haakon , Vihtakari Mikko , Bluhm Bodil A. , Daase Malin , Gradinger Rolf , Melnikov Igor A.
Published: October 2021

Sea-ice macrofauna includes ice amphipods and benthic amphipods, as well as mysids. Amphipods are important components of the sympagic food web, which is fuelled by the production of ice algae. Data on the diversity of sea-ice biota have been collected as a part of scientific expeditions over decades, and here we present a pan-Arctic analysis of data on ice-associated amphipods and mysids assimilated over 35 years (1977–2012). The composition of species differed among the 13 locations around the Arctic, with main differences between basins and shelves and also between communities in drift ice and landfast sea ice. The sea ice has been dramatically reduced in extent and thickness during the recorded period, which has resulted in reduced abundance of ice amphipods as well as benthic amphipods in sea ice from the 1980’s to the 2010’s. The decline mainly involved Gammarus wilkitzkii coinciding with the disappearance of much of the multiyear sea ice, which is an important habitat for this long-lived species. Benthic amphipods were most diverse, and also showed a decline over the time-span. They had higher abundance closer to land where they are associated with landfast ice. However, they also occurred in the Central Arctic Ocean, which is likely related to the origin of sea ice over shallow water and subsequent transport in the transpolar ice drift. Recent sampling in the waters east and north of Svalbard has found continued presence of Apherusa glacialis, but almost no G. wilkitzkii. Monitoring by standardized methods is needed to detect further changes in community composition of ice amphipods related to reductions in sea-ice cover and ice type.
Evaluation of Microchip-Based Point-Of-Care Device “Gazelle” for Diagnosis of Sickle Cell Disease in India
Authors: Shrivas Shweta , Patel Madhav , Kumar Rajat , Gwal Anil , Uikey Ramswaroop , Tiwari Shashi Kant , Verma Anil Kumar , Thota Priyaleela , Das Aparup , Bharti Praveen Kumar , Shanmugam Rajasubramaniam
Published: October 2021

Sickle cell disease is a major public health problem in India. Lack of rapid and reliable diagnostic methods result in many avoidable deaths in affected population. Current diagnostic tools are laboratory based, expensive and need trained manpower. Here, we evaluated the performance of a microchip-based cellulose acetate electrophoresis test, “Gazelle” in the tribal-dominated Indian states of Chhattisgarh and Madhya Pradesh. A total of 1,050 patients were screened by sickle cell solubility, hemoglobin (cellulose acetate) electrophoresis, high-performance liquid chromatography (HPLC) and Gazelle. Of the total 1,027 test results obtained, 960 tests were “Valid” (93.5%) and included in the analysis. Gazelle identified all patients with disease (HbSS and Thalassemia Major) with 100% accuracy. Gazelle demonstrated 100% sensitivity when comparing sickle cell disease (SCD) vs. sickle cell trait and SCD vs. normal. Specificity was 98.9% and 99.5% when comparing SCD vs. trait and trait vs. normal, respectively. Specificity was 99.8% when comparing SCD vs. normal and sensitivity was 99.3% when comparing trait vs. normal. Overall, Gazelle yielded a high accuracy (99.0%) compared to reference standard tests (hemoglobin electrophoresis and HPLC). Gazelle is a low-cost, rapid diagnostic test with high accuracy for detecting SCD both quantitatively and qualitatively. Gazelle can be a potential screening tool for the rapid diagnosis in resource limited settings and developing countries with high burden of hemoglobin disorders.
Controversials of Microscopic Colitis
Authors: Mihaly Emese , Patai Árpád , Tulassay Zsolt
Published: October 2021

Microscopic colitis (MC) has become a disease with increased awareness due to the availability of new data about the pathogenesis, diagnosis and therapy of this disease. The incidence of MC is increasing, reaching the incidence of the inflammatory bowel disease (IBD) in some populations. However, some aspects of MC are still controversial. It is unknown whether the changes of microbiome play a role in the pathogenesis and what is in the background of the different subtypes of disease that can transform into each other. Is there a connection between MC and IBD or why the histological changes do not follow the clinical activity? We do not know what the etiology of the incomplete MC is, and what its natural course is. The association of MC with celiac disease is well-known- is there a common pathogenesis? The MC treatment is budesonide. Its effectiveness is high, but the relapse rate is high, as well. Why would biologics be effective in these cases when budesonide is not? This mini-review makes an attempt to summarize the data about MC and highlight that there are still unanswered questions in the pathogenesis, diagnosis and therapy of the disease, which can initiate further investigations in the future.