bluuebunny/crossref_metadata_2025 huggingface dataset:
Transcriptomic Signature of Human Embryonic Thyroid Reveals Transition From Differentiation to Functional Maturation
Authors: Dom Geneviève , Dmitriev Petr , Lambot Marie-Alexandra , Van Vliet Guy , Glinoer Daniel , Libert Frédérick , Lefort Anne , Dumont Jacques E. , Maenhaut Carine
Published: June 2021

The human thyroid gland acquires a differentiation program as early as weeks 3–4 of embryonic development. The onset of functional differentiation, which manifests by the appearance of colloid in thyroid follicles, takes place during gestation weeks 10–11. By 12–13 weeks functional differentiation is accomplished and the thyroid is capable of producing thyroid hormones although at a low level. During maturation, thyroid hormones yield increases and physiological mechanisms of thyroid hormone synthesis regulation are established. In the present work we traced the process of thyroid functional differentiation and maturation in the course of human development by performing transcriptomic analysis of human thyroids covering the period of gestation weeks 7–11 and comparing it to adult human thyroid. We obtained specific transcriptomic signatures of embryonic and adult human thyroids by comparing them to non-thyroid tissues from human embryos and adults. We defined a non-TSH (thyroid stimulating hormone) dependent transition from differentiation to maturation of thyroid. The study also sought to shed light on possible factors that could replace TSH, which is absent in this window of gestational age, to trigger transition to the emergence of thyroid function. We propose a list of possible genes that may also be involved in abnormalities in thyroid differentiation and/or maturation, hence leading to congenital hypothyroidism. To our knowledge, this study represent the first transcriptomic analysis of human embryonic thyroid and its comparison to adult thyroid.
Identification of ZNF26 as a Prognostic Biomarker in Colorectal Cancer by an Integrated Bioinformatic Analysis
Authors: Liu Jiaxin , Li Yimin , Gan Yaqi , Xiao Qing , Tian Ruotong , Shu Guang , Yin Gang
Published: June 2021

The dysregulation of transcriptional factors (TFs) leads to malignant growth and the development of colorectal cancer (CRC). Herein, we sought to identify the transcription factors relevant to the prognosis of colorectal cancer patients. We found 526 differentially expressed TFs using the TCGA database of colorectal cancer patients (n = 544) for the differential analysis of TFs (n = 1,665) with 210 upregulated genes as well as 316 downregulated genes. Subsequently, GO analysis and KEGG pathway analysis were performed for these differential genes for investigating their pathways and function. At the same time, we established a genetic risk scoring model for predicting the overall survival (OS) by using the mRNA expression levels of these differentially regulated TFs, and defined the CRC into low and high-risk categories which showed significant survival differences. The genetic risk scoring model included four high-risk genes (HSF4, HEYL, SIX2, and ZNF26) and two low-risk genes (ETS2 and SALL1), and validated the OS in two GEO databases (p = 0.0023 for the GSE17536, p = 0.0193 for the GSE29623). To analyze the genetic and epigenetic changes of these six risk-related TFs, a unified bioinformatics analysis was conducted. Among them, ZNF26 is progressive in CRC and its high expression is linked with a poor diagnosis as well. Knockdown of ZNF26 inhibits the proliferative capacity of CRC cells. Moreover, the positive association between ZNF26 and cyclins (CDK2, CCNE2, CDK6, CHEK1) was also identified. Therefore, as a novel biomarker, ZNF26 may be a promising candidate in the diagnosis and prognostic evaluation of colorectal cancer.
The Emerging Roles of Pericytes in Modulating Tumor Microenvironment
Authors: Sun Ruipu , Kong Xiangzhan , Qiu Xiaoyi , Huang Cheng , Wong Ping-Pui
Published: June 2021

Pericytes (PCs), known as mural cells, play an important blood vessel (BV) supporting role in regulating vascular stabilization, permeability and blood flow in microcirculation as well as blood brain barrier. In carcinogenesis, defective interaction between PCs and endothelial cells (ECs) contributes to the formation of leaky, chaotic and dysfunctional vasculature in tumors. However, recent works from other laboratories and our own demonstrate that the direct interaction between PCs and other stromal cells/cancer cells can modulate tumor microenvironment (TME) to favor cancer growth and progression, independent of its BV supporting role. Furthermore, accumulating evidence suggests that PCs have an immunomodulatory role. In the current review, we focus on recent advancement in understanding PC’s regulatory role in the TME by communicating with ECs, immune cells, and tumor cells, and discuss how we can target PC’s functions to re-model TME for an improved cancer treatment strategy.
The Pyroptosis-Related Signature Predicts Prognosis and Indicates Immune Microenvironment Infiltration in Gastric Cancer
Authors: Shao Wei , Yang Zongcheng , Fu Yue , Zheng Lixin , Liu Fen , Chai Li , Jia Jihui
Published: June 2021

Gastric cancer (GC) is one of the leading causes of cancer-related deaths and shows high levels of heterogeneity. The development of a specific prognostic model is important if we are to improve treatment strategies. Pyroptosis can arise in response to H. pylori, a primary carcinogen, and also in response to chemotherapy drugs. However, the prognostic evaluation of GC to pyroptosis is insufficient. Consensus clustering by pyroptosis-related regulators was used to classify 618 patients with GC from four GEO cohorts. Following Cox regression with differentially expressed genes, our prognosis model (PS-score) was built by LASSO-Cox analysis. The TCGA-STAD cohort was used as the validation set. ESTIMATE, CIBERSORTx, and EPIC were used to investigate the tumor microenvironment (TME). Immunotherapy cohorts by blocking PD1/PD-L1 were used to investigate the treatment response. The subtyping of GC based on pyroptosis-related regulators was able to classify patients according to different clinical traits and TME. The difference between the two subtypes identified in this study was used to develop a prognosis model which we named “PS-score.” The PS-score could predict the prognosis of patients with GC and his/her overall survival time. A low PS-score implies greater inflammatory cell infiltration and better response of immunotherapy by PD1/PD-L1 blockers. Our findings provide a foundation for future research targeting pyroptosis and its immune microenvironment to improve prognosis and responses to immunotherapy.
Scaling Laws for Mitotic Chromosomes
Authors: Kramer Eric M. , Tayjasanant P. A. , Cordone Bethan
Published: June 2021

During mitosis in higher eukaryotes, each chromosome condenses into a pair of rod-shaped chromatids. This process is co-regulated by the activity of several gene families, and the underlying biophysics remains poorly understood. To better understand the factors regulating chromosome condensation, we compiled a database of mitotic chromosome size and DNA content from the tables and figures of >200 published papers. A comparison across vertebrate species shows that chromosome width, length and volume scale with DNA content to the powers ∼1/4, ∼1/2, and ∼1, respectively. Angiosperms (flowering plants) show a similar length scaling, so this result is not specific to vertebrates. Chromosome shape and size thus satisfy two conditions: (1) DNA content per unit volume is approximately constant and (2) the cross-sectional area increases proportionately with chromosome length. Since viscous drag forces during chromosome movement are expected to scale with length, we hypothesize that the cross-section increase is necessary to limit the occurrence of large chromosome elongations that could slow or stall mitosis. Lastly, we note that individual vertebrate karyotypes typically exhibit a wider range of chromosome lengths as compared with angiosperms.
Metabolic Remodeling in Glioma Immune Microenvironment: Intercellular Interactions Distinct From Peripheral Tumors
Authors: Qiu Runze , Zhong Yue , Li Qingquan , Li Yingbin , Fan Hongwei
Published: June 2021

During metabolic reprogramming, glioma cells and their initiating cells efficiently utilized carbohydrates, lipids and amino acids in the hypoxic lesions, which not only ensured sufficient energy for rapid growth and improved the migration to normal brain tissues, but also altered the role of immune cells in tumor microenvironment. Glioma cells secreted interferential metabolites or depriving nutrients to injure the tumor recognition, phagocytosis and lysis of glioma-associated microglia/macrophages (GAMs), cytotoxic T lymphocytes, natural killer cells and dendritic cells, promoted the expansion and infiltration of immunosuppressive regulatory T cells and myeloid-derived suppressor cells, and conferred immune silencing phenotypes on GAMs and dendritic cells. The overexpressed metabolic enzymes also increased the secretion of chemokines to attract neutrophils, regulatory T cells, GAMs, and dendritic cells, while weakening the recruitment of cytotoxic T lymphocytes and natural killer cells, which activated anti-inflammatory and tolerant mechanisms and hindered anti-tumor responses. Therefore, brain-targeted metabolic therapy may improve glioma immunity. This review will clarify the metabolic properties of glioma cells and their interactions with tumor microenvironment immunity, and discuss the application strategies of metabolic therapy in glioma immune silence and escape.
Targeted Mitochondrial Therapy With Over-Expressed MAVS Protein From Mesenchymal Stem Cells: A New Therapeutic Approach for COVID-19
Authors: Babajani Amirhesam , Hosseini-Monfared Pooya , Abbaspour Samin , Jamshidi Elham , Niknejad Hassan
Published: June 2021

The SARS-CoV-2, the virus that causes COVID-19, has infected millions of people worldwide. The symptoms of this disease are primarily due to pulmonary involvement, uncontrolled tissue inflammation, and inadequate immune response against the invader virus. Impaired interferon (IFN) production is one of the leading causes of the immune system’s inability to control the replication of the SARS-CoV-2. Mitochondria play an essential role in developing and maintaining innate cellular immunity and IFN production. Mitochondrial function is impaired during cellular stress, affecting cell bioenergy and innate immune responses. The mitochondrial antiviral-signaling protein (MAVS), located in the outer membrane of mitochondria, is one of the key elements in engaging the innate immune system and interferon production. Transferring healthy mitochondria to the damaged cells by mesenchymal stem cells (MSCs) is a proposed option for regenerative medicine and a viable treatment approach to many diseases. In addition to mitochondrial transport, these cells can regulate inflammation, repair the damaged tissue, and control the pathogenesis of COVID-19. The immune regulatory nature of MSCs dramatically reduces the probability of an immune rejection. In order to induce an appropriate immune response against the SARS-CoV-2, we hypothesize to donate mitochondria to the host cells of the virus. We consider MSCs as an appropriate biological carrier for mitochondria. Besides, enhancing the expression of MAVS protein in MSCs and promoting the expression of SARS-CoV-2 viral spike protein as a specific ligand for ACE2+ cells will improve IFN production and innate immune responses in a targeted manner.
Left Anterior Fascicular Block After Transcatheter Closure of Ventricular Septal Defect in Children
Authors: Wu Zhijun , Yang Penghui , Xiang Ping , Ji Xiaojuan , Tian Jie , Li Mi
Published: June 2021

Background: Arrhythmia is the most common complication after transcatheter closure of a ventricular septal defect (VSD). However, the effects of postprocedural left anterior fascicular block are not clear. This study presents the clinical characteristics, prognosis, and related risk factors of left anterior fascicular block after transcatheter closure of a VSD in children.

Methods: The clinical and follow-up data of the patients in the Heart Center of Children's Hospital of Chongqing Medical University from June 2009 to October 2018 were reviewed. And 30 cases were eligible out of all 1,371 cases.

Results: An electrocardiogram showed a left anterior fascicular block within 3 days, and most patients gradually returned to normal within 1–2 years, showing a dynamic change. Left ventricular end-diastolic dimension Z-score ranged from −2 to 2 in all children, and no decrease of left ventricular ejection fraction was found in all children. The high ratio between VSD size and body surface area [p < 0.05, odds ratio (OR) 2.6, 95% CI: 1.136–6.113] and large diameter difference between the occluder size and VSD size (p < 0.05, OR 2.1, 95% CI: 1.036–4.609) were independent risk factors for postprocedural left anterior fascicular block.

Conclusions: The incidence of postprocedural left anterior fascicular block is not that low, and the overall prognosis is quite good at the current follow-up stage. No progressive severity has been found, such as complete left bundle branch block, double (triple) bundle branch block, and atrioventricular block, to have an influence on cardiac systolic and diastolic function.
Effects of Transapical Transcatheter Mitral Valve Implantation
Authors: Hsiung Ming-Chon , Yin Wei-Hsian , Lee Yung-Tsai , Tsao Tien-Ping , Lee Kuo-Chen , Huang Kuan-Chih , Chen Pei-En , Chiang Wei-Hsuan , Tung Tao-Hsin , Wei Jeng
Published: June 2021

Purpose: In this study, transapical transcatheter mitral valve-in-valve implantation (TAMVI) was compared with surgical redo mitral valve replacement (SRMVR) in terms of clinical outcomes.

Methods: We retrospectively identified patients with degenerated mitral bioprosthesis or failed annuloplasty rings who underwent redo SRMVR or TAMVI at our medical center. Clinical outcomes were based on echocardiography results.

Results: We retrospectively identified patients with symptomatic mitral bioprosthetic valve dysfunction (n = 58) and failed annuloplasty rings (n = 14) who underwent redo SRMVR (n = 36) or TAMVI (n = 36). The Society of Thoracic Surgeons Predicted Risk of Mortality scores were higher in the TAMVI group (median: 9.52) than in the SRMVR group (median: 5.59) (p-value = 0.02). TAMVI patients were more severe in New York Heart Association (p-value = 0.04). The total procedure time (skin to skin) and length of stay after procedures were significantly shorter in the TAMVI group, and no significant difference in mortality was noted after adjustment for confounding factors (p-value = 0.11). The overall mean mitral valve pressure gradient was lower in the TAMVI group than in the SRMVR group at 24 months (p < 0.01). Both groups presented a decrease in the severity of mitral and tricuspid regurgitation at 3–24 months.

Conclusions: In conclusion, the statistical analysis is still not robust enough to make a claim that TAMVI is an appropriate alternative. The outcome of the patient appears only to be related to the patient's pre-operative STS score. Additional multi-center, longitudinal studies are warranted to adequately assess the effect of TAMVI.
Recency of Faulting and Subsurface Architecture of the San Diego Bay Pull-Apart Basin, California, USA
Authors: Singleton Drake M. , Maloney Jillian M. , Brothers Daniel S. , Klotsko Shannon , Driscoll Neal W. , Rockwell Thomas K.
Published: June 2021

In Southern California, plate boundary motion between the North American and Pacific plates is distributed across several sub-parallel fault systems. The offshore faults of the California Continental Borderland (CCB) are thought to accommodate ∼10–15% of the total plate boundary motion, but the exact distribution of slip and the mechanics of slip partitioning remain uncertain. The Newport-Inglewood-Rose Canyon fault is the easternmost fault within the CCB whose southern segment splays out into a complex network of faults beneath San Diego Bay. A pull-apart basin model between the Rose Canyon and the offshore Descanso fault has been used to explain prominent fault orientations and subsidence beneath San Diego Bay; however, this model does not account for faults in the southern portion of the bay or faulting east of the bay. To investigate the characteristics of faulting and stratigraphic architecture beneath San Diego Bay, we combined a suite of reprocessed legacy airgun multi-channel seismic profiles and high-resolution Chirp data, with age and lithology controls from geotechnical boreholes and shallow sub-surface vibracores. This combined dataset is used to create gridded horizon surfaces, fault maps, and perform a kinematic fault analysis. The structure beneath San Diego Bay is dominated by down-to-the-east motion on normal faults that can be separated into two distinct groups. The strikes of these two fault groups can be explained with a double pull-apart basin model for San Diego Bay. In our conceptual model, the western portion of San Diego Bay is controlled by a right-step between the Rose Canyon and Descanso faults, which matches both observations and predictions from laboratory models. The eastern portion of San Diego Bay appears to be controlled by an inferred step-over between the Rose Canyon and San Miguel-Vallecitos faults and displays distinct fault strike orientations, which kinematic analysis indicates should have a significant component of strike-slip partitioning that is not detectable in the seismic data. The potential of a Rose Canyon-San Miguel-Vallecitos fault connection would effectively cut the stepover distance in half and have important implications for the seismic hazard of the San Diego-Tijuana metropolitan area (population ∼3 million people).
δ60Ni and δ13C Composition of Serpentinites and Carbonates of the Tekirova Ophiolite, Turkey, and Meatiq Ophiolite, Egypt
Authors: Neubeck Anna , Boosman Arjen , Hosgörmez Hakan , Özcan Dogacan , Boskabadi Arman , Ivarsson Magnus , Rouxel Olivier
Published: June 2021

Nickel isotope fractionation patterns in continental ultramafic environments generally show a depletion of δ60Ni in weathered rocks and an enrichment in bedrock samples. The present study focuses on stable Ni isotope fractionation patterns in carbonate-rich, ultramafic ophiolite samples with concomitant fluids at an active serpentinization site in southwestern Turkey, with a comparison to results from an inactive serpentinization site in the Eastern Desert of Egypt with carbonate-rich samples. All solid phase data from the inactive serpentinization area are consistent with previously reported values from serpentinites, whereas the solid precipitates in the active area (SW Turkey) give values slightly heavier than previously reported data. However, the Ni isotopic signatures in the active serpentinization system likely reflect the scavenging of light Ni by iron oxide and carbonate precipitation, as has been previously demonstrated in laboratory coprecipitation experiments. It is also possible that the active system results resemble previous laboratory experimental results that show a relatively strong initial fractionation between fluids and solids, which then diminishes with time due to aging of the precipitates.
The Burial Under Peat Technique: An Innovative Method to Restore Sphagnum Peatlands Impacted by Mineral Linear Disturbances
Authors: Pouliot Kathy , Rochefort Line , LeBlanc Marie-Claire , Guêné-Nanchen Mélina , Beauchemin Alexandre
Published: June 2021

Mineral roads in peatlands change the nature of the substrate, influence the water table level of the peatland on either side of the road and the physicochemical characteristics of the water and peat. These changes can in turn affect plant community composition. The efficiency of an innovative and affordable method for the restoration of peatlands impacted by roads was evaluated: the Burial Under Peat Technique. To be considered effective from an ecological point of view, the technique should meet restoration goals by 1) confining the chemical elements and compounds potentially leaching from the mineral material; 2) creating and maintaining a restored surface elevation similar to the adjacent peatland for optimal rewetting; and 3) re-establishing typical peatland vegetation communities. Three years post-restoration, water sampled at various depths and distances to the buried road presented chemical elements and compounds concentrations similar to the means measured in the pristine surrounding peatland for most of the ions analyzed. The different steps of the technique ensured the reestablishment of an elevation similar to the surrounding peatland. The return of peatland plant communities was slow, mainly due to local factors (e.g., presence of drainage ditches). Furthermore, the Burial Under Peat Technique fulfilled the restoration objectives in re-establishing an acid organic soil. Finally, it is a cost-effective method in comparison to completely removing the mineral material and transporting new material to fill the depression left by the excavation of the road.
Geologic and Structural Evolution of the NE Lau Basin, Tonga: Morphotectonic Analysis and Classification of Structures Using Shallow Seismicity
Authors: Anderson Melissa O. , Norris-Julseth Chantal , Rubin Kenneth H. , Haase Karsten , Hannington Mark D. , Baxter Alan T. , Stewart Margaret S.
Published: June 2021

The transition from subduction to transform motion along horizontal terminations of trenches is associated with tearing of the subducting slab and strike-slip tectonics in the overriding plate. One prominent example is the northern Tonga subduction zone, where abundant strike-slip faulting in the NE Lau back-arc basin is associated with transform motion along the northern plate boundary and asymmetric slab rollback. Here, we address the fundamental question: how does this subduction-transform motion influence the structural and magmatic evolution of the back-arc region? To answer this, we undertake the first comprehensive study of the geology and geodynamics of this region through analyses of morphotectonics (remote-predictive geologic mapping) and fault kinematics interpreted from ship-based multibeam bathymetry and Centroid-Moment Tensor data. Our results highlight two notable features of the NE Lau Basin: 1) the occurrence of widely distributed off-axis volcanism, in contrast to typical ridge-centered back-arc volcanism, and 2) fault kinematics dominated by shallow-crustal strike slip-faulting (rather than normal faulting) extending over ∼120 km from the transform boundary. The orientations of these strike-slip faults are consistent with reactivation of earlier-formed normal faults in a sinistral megashear zone. Notably, two distinct sets of Riedel megashears are identified, indicating a recent counter-clockwise rotation of part of the stress field in the back-arc region closest to the arc. Importantly, the Riedel structures identified in this study directly control the development of complex volcanic-compositional provinces, which are characterized by variably-oriented spreading centers, off-axis volcanic ridges, extensive lava flows, and point-source rear-arc volcanoes. This study adds to our understanding of the geologic and structural evolution of modern backarc systems, including the association between subduction-transform motions and the siting and style of seafloor volcanism.
The Influences of TSH Stimulation Level, Stimulated Tg Level and Tg/TSH Ratio on the Therapeutic Effect of 131I Treatment in DTC Patients
Authors: Zheng Wei , Rui Zhongying , Wang Xuan , Li Ning , Tan Jian , Liu Wei
Published: June 2021

Purpose

To study the influences of pre-ablation TSH stimulation level, sTg and sTg/TSH ratio on the therapeutic effect of the first 131I treatment in DTCs.

Methods

According to the thyroid stimulating hormone (TSH) levels (mU/l), all the 479 differentiated thyroid cancer (DTC) patients were divided into two groups: TSH < 30 and TSH ≥ 30. The TSH ≥ 30 group was divided into three subgroups: 30 ≤ TSH < 60, 60 ≤ TSH < 90 and TSH ≥ 90. The clinical features and the therapeutic effects of the first 131I treatment were analyzed. The cutoffs of stimulated thyroglobulin (sTg) and sTg/TSH ratio were calculated to predict the therapeutic effect of 131I treatment.

Results

Among the three subgroups, the TSH ≥ 90 subgroup was younger and less likely to be associated with cervical lymph node metastasis (LNM). The postoperative levothyroxine (L-T4) dose in the 60 ≤ TSH < 90 subgroup was the lowest. Between the two groups, patients in the TSH < 30 group had higher postoperative L-T4 dose and longer thyroid hormone withdrawal (THW) time. The excellent response rates six months after the first 131I treatment among the three subgroups and between the two groups were not of statistical significance. The distribution of different TSH stimulation levels among each response group was similar. The cutoffs for the better therapeutic effect of the first 131I treatment in sTg and sTg/TSH were < 9.51 ng/ml and < 0.11, respectively. Both univariate and multivariate logistic regressions showed that cervical LNM, distant metastasis, higher sTg and higher sTg/TSH ratio predicted poorer therapeutic effect.

Conclusions

There was no significant influence of TSH stimulation levels before the first 131I treatment on the therapeutic effect of DTC. The sTg/TSH ratio can be considered as another predictor of 131I therapeutic effect.
CRISPR/Cas9 ADCY7 Knockout Stimulates the Insulin Secretion Pathway Leading to Excessive Insulin Secretion
Authors: Alhaidan Yazeid , Christesen Henrik Thybo , Lundberg Elena , Balwi Mohammed A. Al , Brusgaard Klaus
Published: June 2021

Aim

Despite the enormous efforts to understand Congenital hyperinsulinism (CHI), up to 50% of the patients are genetically unexplained. We aimed to functionally characterize a novel candidate gene in CHI.

Patient

A 4-month-old boy presented severe hyperinsulinemic hypoglycemia. A routine CHI genetic panel was negative.

Methods

A trio-based whole-exome sequencing (WES) was performed. Gene knockout in the RIN-m cell line was established by CRISPR/Cas9. Gene expression was performed using real-time PCR.

Results

Hyperinsulinemic hypoglycemia with diffuse beta-cell involvement was demonstrated in the patient, who was diazoxide-responsive. By WES, compound heterozygous variants were identified in the adenylyl cyclase 7, ADCY7 gene p.(Asp439Glu) and p.(Gly1045Arg). ADCY7 is calcium-sensitive, expressed in beta-cells and converts ATP to cAMP. The variants located in the cytoplasmic domains C1 and C2 in a highly conserved and functional amino acid region. RIN-m(-/-Adcy7) cells showed a significant increase in insulin secretion reaching 54% at low, and 49% at high glucose concentrations, compared to wild-type. In genetic expression analysis Adcy7 loss of function led to a 34.1-fold to 362.8-fold increase in mRNA levels of the insulin regulator genes Ins1 and Ins2 (p ≤ 0.0002), as well as increased glucose uptake and sensing indicated by higher mRNA levels of Scl2a2 and Gck via upregulation of Pdx1, and Foxa2 leading to the activation of the glucose stimulated-insulin secretion (GSIS) pathway.

Conclusion

This study identified a novel candidate gene, ADCY7, to cause CHI via activation of the GSIS pathway.
Effectiveness of a Yoga-Based Lifestyle Protocol (YLP) in Preventing Diabetes in a High-Risk Indian Cohort: A Multicenter Cluster-Randomized Controlled Trial (NMB-Trial)
Authors: Raghuram Nagarathna , Ram Venkat , Majumdar Vijaya , SK Rajesh , Singh Amit , Patil Suchitra , Anand Akshay , Judu Ilavarasu , Bhaskara Srikanta , Basa Jagannadha Rao , Nagendra Hongasandra Ramarao
Published: June 2021

Introduction

Though several lines of evidence support the utility of yoga-based interventions in diabetes prevention, most of these studies have been limited by methodological issues, primarily sample size inadequacy. Hence, we tested the effectiveness of yoga-based lifestyle intervention against diabetes risk reduction in multicentre, large community settings of India, through a single-blind cluster-randomized controlled trial, Niyantrita Madhumeha Bharat Abhiyan (NMB).

Research Design and Methods

NMB-trial is a multicentre cluster-randomized trial conducted in 80 clusters [composed of rural units (villages) and urban units (Census Enumeration Blocks)] randomly assigned in a 1:1 ratio to intervention and control groups. Participants were individuals (age, 20–70 years) with prediabetes (blood HbA1c values in the range of 5.7–6.4%) and IDRS ≥ 60. The intervention included the practice of yoga-based lifestyle modification protocol (YLP) for 9 consecutive days, followed by daily home and weekly supervised practices for 3 months. The control cluster received standard of care advice for diabetes prevention. Statistical analyses were performed on an intention-to-treat basis, using available and imputed datasets. The primary outcome was the conversion from prediabetes to diabetes after the YLP intervention of 3 months (diagnosed based upon HbA1c cutoff >6.5%). Secondary outcome included regression to normoglycemia with HbA1c <5.7%.

Results

A total of 3380 (75.96%) participants were followed up at 3 months. At 3 months post-intervention, overall, diabetes developed in 726 (21.44%) participants. YLP was found to be significantly effective in halting progression to diabetes as compared to standard of care; adjusted RRR was 63.81(95% CI = 56.55–69.85). The YLP also accelerated regression to normoglycemia [adjusted Odds Ratio (adjOR) = 1.20 (95% CI, 1.02–1.43)]. Importantly, younger participants (≤40 years) were found to regress to normoglycemia more effectively than the older participants Pinteraction<0.001.

Conclusion

Based on the significant risk reduction derived from the large sample size, and the carefully designed randomized yoga-based intervention on high-risk populations, the study is a preliminary but strong proof-of-concept for yoga as a potential lifestyle-based treatment to curb the epidemic of diabetes. The observed findings also indicate a potential of YLP for diabetes prevention in low/moderate risk profile individuals that needs large-scale validation.

Trial Registration

Clinical Trial Registration Number: CTRI/2018/03/012804.
Low Moisture Anhydrous Ammonia Pretreatment of Four Lignocellulosic Materials—Distillers Dried Grains With Solubles, Corn Gluten Feed, Corn Fiber, and Oil Palm Frond
Authors: Mahmud Nazira , Rosentrater Kurt A.
Published: June 2021

Lignin and hemicellulose structures in cellulosic materials serve as a barrier for enzyme reactions. A pretreatment step is often needed to break these components to allow the biomass to be utilized as a source of value-added products. Various available pretreatment methods possess common drawbacks of the high amount of liquid and chemical requirements, harsh process conditions, and the high amount of waste produced, which driving up the production costs of bioproducts. Low moisture anhydrous ammonia (LMAA) pretreatment capable of eliminating those drawbacks. In this study, Distillers Dried Grains with Solubles (DDGS), corn gluten feed (CGF), corn fiber (CF), and oil palm frond (OPF) with different moisture contents were subjected to LMAA pretreatment at the specific ammonia loading rate, 1 h ammoniation, and 75°C incubation temperature. This pretreatment successfully decreased the lignin content of the materials, increased their percentage of α-cellulose, and improved enzymatic digestibility for most of the materials tested. The effect of moisture content (30 and 50% db) was found to be more significant than that of incubation time (24 and 72 h).
Modeling Microbial Adaptations to Nutrient Limitation During Litter Decomposition
Authors: Manzoni Stefano , Chakrawal Arjun , Spohn Marie , Lindahl Björn D.
Published: June 2021

Microbial decomposers face large stoichiometric imbalances when feeding on nutrient-poor plant residues. To meet the challenges of nutrient limitation, microorganisms might: (i) allocate less carbon (C) to growth vs. respiration or excretion (i.e., flexible C-use efficiency, CUE), (ii) produce extracellular enzymes to target compounds that supply the most limiting element, (iii) modify their cellular composition according to the external nutrient availability, and (iv) preferentially retain nutrients at senescence. These four resource use modes can have different consequences on the litter C and nitrogen (N) dynamics–modes that selectively remove C from the system can reduce C storage in soil, whereas modes that delay C mineralization and increase internal N recycling could promote storage of C and N. Since we do not know which modes are dominant in litter decomposers, we cannot predict the fate of C and N released from plant residues, in particular under conditions of microbial nutrient limitation. To address this question, we developed a process-based model of litter decomposition in which these four resource use modes were implemented. We then parameterized the model using ∼80 litter decomposition datasets spanning a broad range of litter qualities. The calibrated model variants were able to capture most of the variability in litter C, N, and lignin fractions during decomposition regardless of which modes were included. This suggests that different modes can lead to similar litter decomposition trajectories (thanks to the multiple alternative resource acquisition pathways), and that identification of dominant modes is not possible using “standard” litter decomposition data (an equifinality problem). Our results thus point to the need of exploring microbial adaptations to nutrient limitation with empirical estimates of microbial traits and to develop models flexible enough to consider a range of hypothesized microbial responses.
Identification of Novel Biallelic TLE6 Variants in Female Infertility With Preimplantation Embryonic Lethality
Authors: Zhang Manyu , Liu Chunyu , Chen Beili , Lv Mingrong , Zou Huijuan , Liu Yajing , Gao Yang , Wang Tianjuan , Xing Qiong , Zhu Yutong , Wu Huan , Zhang Zhiguo , Zhou Ping , Wei Zhaolian , He Xiaojin , Xu Yuping , Cao Yunxia
Published: June 2021

Preimplantation embryonic lethality is a rare cause of primary female infertility. It has been reported that variants in the transducin-like enhancer of split 6 (TLE6) gene can lead to preimplantation embryonic lethality. However, the incidence of TLE6 variants in patients with preimplantation embryonic lethality is not fully understood. In this study, we identified four patients carrying novel biallelic TLE6 variants in a cohort of 28 patients with preimplantation embryonic lethality by whole-exome sequencing and bioinformatics analysis, accounting for 14.29% (4/28) of the cohort. Immunofluorescence showed that the TLE6 levels in oocytes from patients were much lower than in normal control oocytes, suggesting that the variants result in the lower expression of the TLE6 protein in oocytes. In addition, a retrospective analysis showed that the four patients underwent a total of nine failures of in vitro fertilization and intracytoplasmic sperm injection attempts, and one of them became pregnant on the first attempt using donated oocytes. Our study extends the genetic spectrum of female infertility caused by variants in TLE6 and further confirms previously reported findings that TLE6 plays an essential role in early embryonic development. In such case, oocyte donation may be the preferred treatment.
Asymmetric Somatic Hybridization Affects Synonymous Codon Usage Bias in Wheat
Authors: Xu Wenjing , Li Yingchun , Li Yajing , Liu Chun , Wang Yanxia , Xia Guangmin , Wang Mengcheng
Published: June 2021

Asymmetric somatic hybridization is an efficient strategy for crop breeding by introducing exogenous chromatin fragments, which leads to whole genomic shock and local chromosomal shock that induces genome-wide genetic variation including indel (insertion and deletion) and nucleotide substitution. Nucleotide substitution causes synonymous codon usage bias (SCUB), an indicator of genomic mutation and natural selection. However, how asymmetric somatic hybridization affects SCUB has not been addressed. Here, we explored this issue by comparing expressed sequence tags of a common wheat cultivar and its asymmetric somatic hybrid line. Asymmetric somatic hybridization affected SCUB and promoted the bias to A- and T-ending synonymous codon (SCs). SCUB frequencies in chromosomes introgressed with exogenous fragments were comparable to those in chromosomes without exogenous fragments, showing that exogenous fragments had no local chromosomal effect. Asymmetric somatic hybridization affected SCUB frequencies in indel-flanking sequences more strongly than in non-flanking sequences, and this stronger effect was present in both chromosomes with and without exogenous fragments. DNA methylation-driven SCUB shift was more pronounced than other SC pairs. SCUB shift was similar among seven groups of allelic chromosomes as well as three sub-genomes. Our work demonstrates that the SCUB shift induced by asymmetric somatic hybridization is attributed to the whole genomic shock, and DNA methylation is a putative force of SCUB shift during asymmetric somatic hybridization. Asymmetric somatic hybridization provides an available method for deepening the nature of SCUB shift and genetic variation induced by genomic shock.
Assembling Disease Networks From Causal Interaction Resources
Authors: Cesareni Gianni , Sacco Francesca , Perfetto Livia
Published: June 2021

The development of high-throughput high-content technologies and the increased ease in their application in clinical settings has raised the expectation of an important impact of these technologies on diagnosis and personalized therapy. Patient genomic and expression profiles yield lists of genes that are mutated or whose expression is modulated in specific disease conditions. The challenge remains of extracting from these lists functional information that may help to shed light on the mechanisms that are perturbed in the disease, thus setting a rational framework that may help clinical decisions. Network approaches are playing an increasing role in the organization and interpretation of patients' data. Biological networks are generated by connecting genes or gene products according to experimental evidence that demonstrates their interactions. Till recently most approaches have relied on networks based on physical interactions between proteins. Such networks miss an important piece of information as they lack details on the functional consequences of the interactions. Over the past few years, a number of resources have started collecting causal information of the type protein A activates/inactivates protein B, in a structured format. This information may be represented as signed directed graphs where physiological and pathological signaling can be conveniently inspected. In this review we will (i) present and compare these resources and discuss the different scope in comparison with pathway resources; (ii) compare resources that explicitly capture causality in terms of data content and proteome coverage (iii) review how causal-graphs can be used to extract disease-specific Boolean networks.
The Adverse Impact of Tumor Microenvironment on NK-Cell
Authors: Hu Ziming , Xu Xiuxiu , Wei Haiming
Published: June 2021

NK cells are considered an important component of innate immunity, which is the first line of defensing against tumors and viral infections in the absence of prior sensitization. NK cells express an array of germline-encoded receptors, which allow them to eliminate abnormal cells and were previously considered a homogenous population of innate lymphocytes, with limited phenotypic and functional diversity. Although their characteristics are related to their developmental origins, other factors, such as tumors and viral infections, can influence their phenotype. Here, we provide an overview of NK cells in the context of the tumor microenvironment, with a primary focus on their phenotypes, functions, and roles in tumor micro-environment. A comprehensive understanding of NK cells in the tumor microenvironment will provide a theoretical basis for the development of NK cell immunotherapy.
How Children Are Protected From COVID-19? A Historical, Clinical, and Pathophysiological Approach to Address COVID-19 Susceptibility
Authors: Massalska Magdalena Anna , Gober Hans-Jürgen
Published: June 2021

The origin and the global spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing coronavirus disease 2019 (COVID-19) in early 2020 was accompanied by high rates of mortality in regions belonging to the ancient silk road, such as the south of China, Iran, Turkey and the northern parts of Italy. However, children seem to be spared in the epidemic as very small percentage worldwide being ill. The protection of children and neonates suggests the involvement of a specific component of adaptive immunity present at early development. Native immunoglobulin belonging to the class of IgM is abundantly present in neonates and children and is known for its recognition of self- and altered self-antigens. Native IgM may be able to neutralize virus by the recognition of endogenous “danger signal” encoded in the viral envelope and originally imprinted in the membranes of infected and stressed cells. Noteworthy, thrombosis and vasculitis, two symptoms in severely affected adult and pediatric patients are shared between COVID-19 and patients with Behcet’s disease, an autoimmune disorder exhibiting a region-specific prevalence in countries of the former silk road. Molecular mechanisms and clinical indicators suggest reactive oxygen species as trigger factor for severe progression of COVID-19 and establish a link to the innate immune defense against bacteria. The selective pressure exerted by bacterial pathogens may have shaped the genetics of inhabitants at this ancient trade route in favor of bacterial defense, to the detriment of severe COVID-19 progression in the 21th century.
Unbiased Analysis of Temporal Changes in Immune Serum Markers in Acute COVID-19 Infection With Emphasis on Organ Failure, Anti-Viral Treatment, and Demographic Characteristics
Authors: Laudanski Krzysztof , Jihane Hajj , Antalosky Brook , Ghani Danyal , Phan Uyen , Hernandez Ruth , Okeke Tony , Wu Junnan , Rader Daniel , Susztak Katalin
Published: June 2021

Identification of novel immune biomarkers to gauge the underlying pathology and severity of COVID-19 has been difficult due to the lack of longitudinal studies. Here, we analyzed serum collected upon COVID-19 admission (t1), 48 hours (t2), and seven days later (t3) using Olink proteomics and correlated to clinical, demographics, and therapeutic data. Older age positively correlated with decorin, pleiotrophin, and TNFRS21 but inversely correlated with chemokine (both C-C and C-X-C type) ligands, monocyte attractant proteins (MCP) and TNFRS14. The burden of pre-existing conditions was positively correlated with MCP-4, CAIX, TWEAK, TNFRS12A, and PD-L2 levels. Individuals with COVID-19 demonstrated increased expression of several chemokines, most notably from the C-C and C-X-C family, as well as MCP-1 and MCP-3 early in the course of the disease. Similarly, deceased individuals had elevated MCP-1 and MCP-3 as well as Gal-9 serum levels. LAMP3, GZMB, and LAG3 at admission correlated with mortality. Only CX3CL13 and MCP-4 correlated positively with APACHE score and length of stay, while decorin, MUC-16 and TNFRSF21 with being admitted to the ICU. We also identified several organ-failure-specific immunological markers, including those for respiratory (IL-18, IL-15, Gal-9) or kidney failure (CD28, VEGF). Treatment with hydroxychloroquine, remdesivir, convalescent plasma, and steroids had a very limited effect on the serum variation of biomarkers. Our study identified several potential targets related to COVID-19 heterogeneity (MCP-1, MCP-3, MCP-4, TNFR superfamily members, and programmed death-ligand), suggesting a potential role of these molecules in the pathology of COVID-19.
Adverse Events Associated With Anti-IL-23 Agents: Clinical Evidence and Possible Mechanisms
Authors: Ru Yi , Ding Xiaojie , Luo Ying , Li Hongjin , Sun Xiaoying , Zhou Mi , Zhou Yaqiong , Kuai Le , Xing Meng , Liu Liu , Luo Yue , Song Jiankun , Chen Jiale , Li Bin , Li Xin
Published: June 2021

Background

Anti-interleukin (IL)-23 agents are widely used for autoimmune disease treatment; however, the safety and risks of specific symptoms have not been systematically assessed.

Objectives

The aim of this study was to summarize the characteristics and mechanisms of occurrence of five immunological and non-immunological adverse events caused by different anti-IL-23 agents.

Methods

The Cochrane Library, EMBASE, PubMed, and Web of Science databases were searched for eligible randomized clinical trials published from inception through May 1, 2020. Randomized clinical trials that reported at least one type of adverse event after treatment were included, regardless of sex, age, ethnicity, and diagnosis. Two investigators independently screened and extracted the characteristics of the studies, participants, drugs, and adverse event types. The Cochrane Handbook was used to assess the methodological quality of the included randomized clinical trials. Heterogeneity was assessed using the I2 statistic. Meta-regression was applied to determine the sources of heterogeneity, and subgroup analysis was used to identify the factors contributing to adverse events.

Results

Forty-eight studies were included in the meta-analysis, comprising 25,624 patients treated with anti-IL-23 agents. Serious immunological or non-immunological adverse events were rare. Anti-IL-12/23-p40 agents appeared to cause adverse events more easily than anti-IL-23-p19 agents. The incidence of cancer did not appear to be related to anti-IL-23 agent treatment, and long-term medication could lead to mental diseases. The prevention of complications should be carefully monitored when administered for over approximately 40 weeks to avoid further adverse reactions, and the incidence of infection was the highest among general immunological adverse events.

Conclusions

The application of anti-IL-23 agents induced a series of immunological and non-immunological adverse events, but these agents tend to be well-tolerated with good safety profiles.
Large-Scale Imputation of KIR Copy Number and HLA Alleles in North American and European Psoriasis Case-Control Cohorts Reveals Association of Inhibitory KIR2DL2 With Psoriasis
Authors: Ahn Richard , Vukcevic Damjan , Motyer Allan , Nititham Joanne , Squire David McG. , Hollenbach Jill A. , Norman Paul J. , Ellinghaus Eva , Nair Rajan P. , Tsoi Lam C. , Oksenberg Jorge , Foerster John , Lieb Wolfgang , Weidinger Stephan , Franke Andre , Elder James T. , Jorgenson Eric , Leslie Stephen , Liao Wilson
Published: June 2021

Killer cell immunoglobulin-like receptors (KIR) regulate immune responses in NK and CD8+ T cells via interaction with HLA ligands. KIR genes, including KIR2DS1, KIR3DL1, and KIR3DS1 have previously been implicated in psoriasis susceptibility. However, these previous studies were constrained to small sample sizes, in part due to the time and expense required for direct genotyping of KIR genes. Here, we implemented KIR*IMP to impute KIR copy number from single-nucleotide polymorphisms (SNPs) on chromosome 19 in the discovery cohort (n=11,912) from the PAGE consortium, University of California San Francisco, and the University of Dundee, and in a replication cohort (n=66,357) from Kaiser Permanente Northern California. Stratified multivariate logistic regression that accounted for patient ancestry and high-risk HLA alleles revealed that KIR2DL2 copy number was significantly associated with psoriasis in the discovery cohort (p ≤ 0.05). The KIR2DL2 copy number association was replicated in the Kaiser Permanente replication cohort. This is the first reported association of KIR2DL2 copy number with psoriasis and highlights the importance of KIR genetics in the pathogenesis of psoriasis.