bluuebunny/crossref_metadata_2025 huggingface dataset:
Along-Strike Variation in Accretion, Non-accretion, and Subduction Erosion Recorded in Rocks of the Jurassic-Neogene Convergent Plate Margin of California
Authors: Wakabayashi John
Published: February 2022

Post-subduction dextral faulting was restored to evaluate the spatial distribution of units of the Franciscan subduction complex of California that formed as a result of subduction accretion. The Franciscan and related rocks of western California exhibit significant along-strike variation in its recording of subduction-accretion processes. Most notably, two segments 830 km apart record subduction erosion associated with low-angle subduction events that took place at ca. 120 Ma and ca. 80–70 Ma in the north and south, respectively. This spatial relationship is not affected by restoration of post-subduction dextral slip because none of the slip passes between the two inboard tectonic windows. Between these segments the subduction complex records net accretion from ca.175 Ma to 12 Ma, but includes horizons recording non-accretion. None of the accreted units of the subduction complex are preserved over the entire length of the subduction complex. One unit, however, correlated on the basis of its structural level in the subduction complex and distinctive detrital zircon age spectra, accreted at about 80–83 Ma extends a strike length of 580 km, an amount increased to 850 km with restoration of post-subduction dextral faulting. The long-strike length of accretion of this unit demonstrates that detrital zircon age populations of subduction complex clastic rocks are poor indicators of strike-slip displacement. Some reaches of the subduction complex include schistose blueschist facies rocks (most Franciscan blueschist facies rocks are not schistose), whereas others do not, and some reaches lack blueschist facies rocks altogether. The significant along-strike variation in the Franciscan and related rock units reflects temporal and spatial differences in history of accretion, non-accretion, subduction erosion, and probably subduction dip. Similar time and space variation in processes and resultant geologic record should be expected for other subduction complexes of the world.
Troubling Unintended Harm of Heroic Discourses in Social Justice Leadership
Authors: Kim Taeyeon , Mauldin Courtney
Published: February 2022

We aim to problematize the ways in which school leaders who seek social justice conflate heroic leadership discourses in their practices. Using qualitative data collected from an urban school principal, this study examines heroic metaphors utilized by the principal when describing social justice leadership and how heroic-centered approaches contradict with achieving social justice goals in school. The findings suggest that the principal’s idea of social justice leadership relies on discourse around “battles to win”, a savior complex, and seeing herself as the central model for driving change. Such heroic discourses reflect the principal’s sole reliance on herself as a savior for her staff and community, which ultimately contradicted the social justice ideals that she sought to accomplish. Our inquiry provides a window to problematize heroic discourse embedded in social justice leadership and address how school leaders must be cognizant to how their practices might conflate with social justice outcomes.
Targeted Re-Sequencing of the 2p21 Locus Identifies Non-Syndromic Cleft Lip Only Novel Susceptibility Gene ZFP36L2
Authors: Li Mu-Jia , Shi Jia-Yu , Zhu Qiu-Shuang , Shi Bing , Jia Zhong-Lin
Published: February 2022

rs7590268 present on the 2p21 locus was identified to be associated with non-syndromic cleft lip with or without cleft palate (NSCL/P) in several populations, including the Chinese Han population, indicating that 2p21 was a susceptibility locus for NSCL/P. However, previous studies have only identified common single-nucleotide polymorphism (SNP) within the THADA gene, neglecting the rare variants and other genes in 2p21; thus, this study was designed to investigate additional variants and novel susceptibility genes in 2p21. A total of 159 NSCL/P patients and 542 controls were recruited in the discovery phase, whereas 1830 NSCL/P patients and 2,436 controls were recruited in the replication phase. After targeted region sequencing, we performed association and burden analyses for the common and rare variants, respectively. Furthermore, RNA-seq, proliferation assay and cell cycle analysis were performed to clarify the possible function of the candidate gene ZFP36L2. Association analysis showed that four SNPs were specifically associated with non-syndromic cleft lip only (NSCLO) and two SNPs were associated with both NSCLO and NSCL/P. Burden analysis indicated that ZFP36L2 was associated with NSCLO (p = .0489, OR = 2.41, 95% CI: 0.98–5.90). Moreover, SNPs in the ZFP36L2 targeted gene JUP were also associated with NSCLO. ZFP36L2 also inhibited cell proliferation and induced G2 phase arrest in the GMSM-K cell line. Therefore, we proposed that ZFP36L2 is a novel susceptibility gene of NSCLO in the 2p21 locus, which could lead to NSCLO by modulating cell proliferation and cycle.
The Promise of DNA Methylation in Understanding Multigenerational Factors in Autism Spectrum Disorders
Authors: Mouat Julia S. , LaSalle Janine M.
Published: February 2022

Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders characterized by impairments in social reciprocity and communication, restrictive interests, and repetitive behaviors. Most cases of ASD arise from a confluence of genetic susceptibility and environmental risk factors, whose interactions can be studied through epigenetic mechanisms such as DNA methylation. While various parental factors are known to increase risk for ASD, several studies have indicated that grandparental and great-grandparental factors may also contribute. In animal studies, gestational exposure to certain environmental factors, such as insecticides, medications, and social stress, increases risk for altered behavioral phenotypes in multiple subsequent generations. Changes in DNA methylation, gene expression, and chromatin accessibility often accompany these altered behavioral phenotypes, with changes often appearing in genes that are important for neurodevelopment or have been previously implicated in ASD. One hypothesized mechanism for these phenotypic and methylation changes includes the transmission of DNA methylation marks at individual chromosomal loci from parent to offspring and beyond, called multigenerational epigenetic inheritance. Alternatively, intermediate metabolic phenotypes in the parental generation may confer risk from the original grandparental exposure to risk for ASD in grandchildren, mediated by DNA methylation. While hypothesized mechanisms require further research, the potential for multigenerational epigenetics assessments of ASD risk has implications for precision medicine as the field attempts to address the variable etiology and clinical signs of ASD by incorporating genetic, environmental, and lifestyle factors. In this review, we discuss the promise of multigenerational DNA methylation investigations in understanding the complex etiology of ASD.
A High-Density Genetic Map and QTL Fine Mapping for Growth- and Sex-Related Traits in Red Swamp Crayfish (Procambarus clarkii)
Authors: Guo Xin-Fen , Zhou Yu-Lin , Liu Min , Li Zhi , Zhou Li , Wang Zhong-Wei , Gui Jian-Fang
Published: February 2022

Red swamp crayfish (Procambarus clarkii) is a commercially important species in global aquaculture and most successfully invasive freshwater shrimp in China. In order to determine the genetic basis of growth- and sex-related traits, a high-density genetic linkage map was constructed using 2b-RAD sequencing technology in a full-sib family. The consensus map contains 4,878 SNP markers assigned to 94 linkage groups (LGs) and spanned 6,157.737 cM with an average marker interval of 1.26 cM and 96.93% genome coverage. The quantitative trait locus (QTL) mapping for growth and sex traits was performed for the first time. QTL mapping uncovers 28 QTLs for growth-related traits in nine LGs, explaining 7.9–14.4% of the phenotypic variation, and identifies some potential candidate growth-related genes such as mih, lamr, golgb1, nurf301, and tbcd1 within the QTL intervals. A single major locus for sex determination was revealed in LG20 that explains 59.3–63.7% of the phenotypic variations. Some candidate sex-related genes, such as vps4bl, ssrf, and acot1, were identified in the QTL intervals and found to be differentially expressed in the muscle tissues between the females and the males. Furthermore, the identified SNPs were revealed to be female heterozygotes, suggesting that red swamp crayfish might have the female heterogametic ZZ/ZW sex determination system. The present study provides a valuable resource for marker-assisted selection and genetic improvement and for further genetic and genomic research in red swamp crayfish.
Research Progress in the Application of Exosomes in Immunotherapy
Authors: Zhang Xiaofang , Xu Donggang , Song Yingqiu , He Rong , Wang Tianlu
Published: February 2022

Exosomes are nanoscale extracellular vesicles (EVs), which are present in all body fluids tested. They are secreted by a variety of cells including macrophages, dendritic cells, mast cells, granulocytes, lymphocytes, and tumor cells. Exosomes secreted by different cells have different biological components and functional characteristics and play an important role in many pathophysiological activities. Recent studies have revealed that exosomes can regulate the occurrence and development of inflammatory immune diseases and tumors by transmitting their unique proteins, lipids, and nucleic acids as signaling molecules to other cells. Exosomes serve as a novel class of diagnostic biomarkers and drug delivery systems with promising applications in immunotherapy, particularly because breakthroughs in nanotechnology have led to the development and exploration of engineered exosomes for immunotargeted therapies. Therefore, here we review the progress being made on the application of exosomes in immunotherapy and its multiple regulatory mechanisms and explore the potential application of exosomes in immunotherapy in the future.
Identification of Sorafenib as a Treatment for Type 1 Diabetes
Authors: Zeng Qin , Song Jianfeng , Wang Dandan , Sun Xiaoxiao , Xiao Yalun , Zhang Haowei , Xiao Yang , Zhou Zhiguang , Deng Tuo
Published: February 2022

Th1 cell activation is considered a key mediator of the pathogenesis of type 1 diabetes. Targeting IL-12-induced Th1 cell differentiation seems to be an effective way to block the development of type 1 diabetes. However, given the critical function of Th1 in the immune system, the potential side effects hinder the application of anti-Th1 therapy in the treatment of type 1 diabetes. To identify safe anti-Th1 treatment(s), we screened the FDA-approved tyrosine kinase inhibitor (TKI) drug library using an IL-12-induced Th1 differentiation cell model. We found that among the TKIs with little effect on T cell viability, sorafenib is the top contender for the inhibition of Th1 differentiation. Treatment of NOD mice with sorafenib significantly impeded the development of type 1 diabetes and ameliorated insulitis, which coincided with a specifically decreased accumulation of Th1 cell population in the pancreas but not in peripheral immune organs. Mechanistically, sorafenib indirectly inhibited janus kinase 2 (JAK2) activity and blocked IL-12-induced phosphorylations of JAK2 and signal transducer and activator of transcription 4 (STAT4). Since sorafenib is classified as an FDA-approved drug, it serves as a preliminary lead point for additional experimentation and may be a promising therapy for type 1 diabetes in humans.
​Circulating Cytokines in Myocardial Infarction Are Associated With Coronary Blood Flow
Authors: Kalinskaya Anna , Dukhin Oleg , Lebedeva Anna , Maryukhnich Elena , Rusakovich Georgy , Vorobyeva Daria , Shpektor Alexander , Margolis Leonid , Vasilieva Elena
Published: February 2022

Background

The level of systemic inflammation correlates with the severity of the clinical course of acute myocardial infarction (AMI). It has been shown that circulating cytokines and endothelial dysfunction play an important role in the process of clot formation. The aim of our study was to assess the concentration of various circulating cytokines, endothelial function and blood clotting in AMI patients depending on the blood flow through the infarction-related artery (IRA).

Methods

We included 75 patients with AMI. 58 presented with ST-elevation myocardial infarction (STEMI) and 17 had non-ST-elevation myocardial infarction (non-STEMI). A flow-mediated dilation test (FMD test), thrombodynamics and rotational thromboelastometry as well as assessment of 14 serum cytokines using xMAP technology were performed.

Findings

Non-STEMI-patients were characterized by higher levels of MDC, MIP-1β, TNF-α. Moreover, we observed that patients with impaired blood flow through the IRA (TIMI flow 0-1) had higher average and initial clot growth rates, earlier onset of spontaneous clots, C-reactive protein (CRP) and IL-10 compared to patients with preserved blood flow through the IRA (TIMI flow 2-3). Patients with TIMI 2-3 blood flow had higher level of IP-10. IL-10 correlated with CRP and pro-inflammatory cytokines levels, initial clot growth rate and clot lysis time in TIMI 0-1 patients. All these differences were statistically significant.

Interpretation

We demonstrated that concentrations of the inflammatory cytokines correlate not only with the form of myocardial infarction (STEMI or non-STEMI), but also with the blood flow through the infarct-related artery. Inflammatory response, functional state of endothelium, and clot formation are closely linked with each other. A combination of these parameters affects the patency of the infarct-related artery.
A Necroptosis-Related Prognostic Model of Uveal Melanoma Was Constructed by Single-Cell Sequencing Analysis and Weighted Co-Expression Network Analysis Based on Public Databases
Authors: Xie Jiaheng , Chen Liang , Tang Qikai , Wei Wei , Cao Yuan , Wu Chuyan , Hang Jing , Zhang Kai , Shi Jingping , Wang Ming
Published: February 2022

Background

Uveal melanoma(UVM) is the most common intraocular malignancy and has a poor prognosis. The clinical significance of necroptosis(NCPS) in UVM is unclear.

Methods

We first identified necroptosis genes in UVM by single-cell analysis of the GSE139829 dataset from the GEO database and weighted co-expression network analysis of TCGA data. COX regression and Lasso regression were used to construct the prognostic model. Then survival analysis, immune microenvironment analysis, and mutation analysis were carried out. Finally, cell experiments were performed to verify the role of ITPA in UVM.

Result

By necroptosis-related prognostic model, UVM patients in both TCGA and GEO cohorts could be classified as high-NCPS and low-NCPS groups, with significant differences in survival time between the two groups (P<0.001). Besides, the high-NCPS group had higher levels of immune checkpoint-related gene expression, suggesting that they might be more likely to benefit from immunotherapy. The cell experiments confirmed the role of ITPA, the most significant gene in the model, in UVM. After ITPA was knocked down, the activity, proliferation, and invasion ability of the MuM-2B cell line were significantly reduced.

Conclusion

Our study can provide a reference for the diagnosis and treatment of patients with UVM.
Behavioural Ecology Traits of Elusive Deep-Diver Whales Unravel a Complex Social Structure Influenced by Female Philopatry and Defence Polygyny
Authors: Badenas Anja , Dinis Ana , Ferreira Rita , Sambolino Annalisa , Hamard Eliette , Berninsone Leonardo G. , Fernandez Marc , Alves Filipe
Published: February 2022

Knowledge of the role of individual associations has provided an insightful understanding of the structures of animal societies, especially in highly social mammals such as primates. Yet, this is unbalanced towards marine mammals, particularly to beaked whales, due to their elusive nature. In addition, information on the fundamental drivers of the social structure of these deep-diving animals is still scarce. Here, the hypothesis of female defence polygyny was tested in Blainville’s beaked whales (Mesoplodon densirostris) and discussed within the context of marine and terrestrial organisms displaying similar patterns, by (i) estimating residency times to obtain information on the movements into and out of the area, (ii) analysing social networks to assess individual association metrics, (iii) measuring the strength of the associations to assess the existence of preferred or avoided relationships among individuals, and (iv) modelling different social structures to address temporal patterns in social relationships. Using a 9-year photographic dataset derived from the pelagic habitat, individual associations were inferred based on likelihood techniques. This approach allowed to infer on the species’ social structure in relation to age class, sex, residency status, and spatio-temporal patterns, which can be a good practice to be applied for other taxa. Heterogeneity in capture probability and residency times was observed between age-sex classes, with adult females exhibiting long-term site fidelity. This suggests different habitat roles and spatial structuring within this social organisation. Strong and long dyadic associations occurred between adult females and immatures, contrarily to between males, and the best-fitting models of the temporal patterns suggested long-lasting and temporary associations. The present findings unravel a complex social structure stratified by age-sex class and influenced by female philopatry and defence polygyny, like an unimale group mating system, which varies from other beaked whales but is similar to some birds, pinnipeds, or non-human primates.
Newborn Screening for Sickle Cell Disease Among Tribal Populations in the States of Gujarat and Madhya Pradesh in India: Evaluation and Outcome Over 6 Years
Authors: Thaker Pallavi , Colah Roshan B. , Patel Jignisha , Raicha Bhavesh , Mistry Abhishek , Mehta Vishal , Italia Yazdi , Desai Shrey , Dave Kapilkumar , Shanmugam Rajasubramaniam , Ghosh Kanjaksha , Mukherjee Malay B.
Published: February 2022

Sickle cell disease (SCD) poses considerable public health problems in India. This study was undertaken to understand the clinical course of SCD among children identified during newborn screening programmes in Gujarat and Madhya Pradesh where the frequency of the HbS gene is high. A total of 8,916 newborn babies 8,411 from Gujarat and 505 from Madhya Pradesh were screened over 6 years (2010–2016) using HPLC and the diagnosis was confirmed by molecular analysis in a subset. A total of 128 babies (122 Gujarat, 6 Madhya Pradesh) were identified with sickle cell disease, of whom 87 (69 HbSS, 18 HbS-β thalassemia) from Gujarat were followed for 0.5–6.6 years. Acute painful events, severe anemia and fever with infections were the major complications and 23 babies required hospitalization. Severe to moderate clinical presentation was found in 13.8% babies with SCD whereas, 86.2% babies had a milder presentation. Presence of ameliorating factors (α-thalassemia and Xmn 1 polymorphism) did not have a discernible effect on the clinical severity. Parents of babies with SCD were educated and counseled for home care. Distribution of mobile phones to 44 families having babies with SCD was beneficial as it allowed regular contact with patients and their families. Genetic counseling to the affected families has increased the awareness and acceptance for prenatal diagnosis and 18 couples opted for prenatal diagnosis in subsequent pregnancies. SCD is not always mild among tribal groups in India. Therefore, facilities for early diagnosis and prophylactic treatment in the tertiary care centers should be made available. The difficulties in regular follow up of the babies in remote rural areas have also been highlighted.
Multisystemic Sarcoidosis Presenting With Leg Ulcers, Pancytopenia, and Polyserositis Was Successfully Treated With Glucocorticoids: A Case Report and Literature Review
Authors: Qiao Xin , He Shan , Altawil Abdullah , Wang Qiu-yue , Kang Jian , Li Wen-yang , Yin Yan
Published: February 2022

Introduction

Sarcoidosis is a chronic granulomatous disease of unknown etiology. A variety of studies have pointed out that almost every part of the body can be affected, but it most often affected the lungs and intrathoracic lymph nodes. However, cases of sarcoidosis involving multiple organs in one patient are rarely reported. We describe a unique case of sarcoidosis, which was characterized by multiorgan involvement, including leg ulcers, splenomegaly, pancytopenia, and polyserositis. Glucocorticoids were effective during the treatment of the above lesions. This case highlights the diversity of clinical manifestations of sarcoidosis and emphasizes the importance of its differential diagnosis and the periodical follow-up. These are crucial to physicians in the diagnosis and treatment of sarcoidosis.

Main Symptoms and Important Clinical Findings

A 30-year-old male complained about intermittent fever 3 years ago. A computed tomographic scan of the chest showed lymphadenopathy in the mediastinum and hilar regions. Routine blood tests showed leukopenia and mild anemia. The pathologic result of mediastinal lymph node biopsy was granulomatous lesions; thus, the patient was diagnosed with type II sarcoidosis without glucocorticoid therapy. In the following 2 years, the patient suffered from intermittent fever accompanied by dyspnea, fatigue, occasional cough, less sputum, and apparent weight loss. Abnormal physical examinations included leg ulcers and splenomegaly. Laboratory and physical tests revealed pancytopenia, polyserositis, and enlargement of lymph nodes. The pathological findings of leg ulceration, pleura, and left supraclavicular lymph node all suggested granulomas.

Diagnosis, Interventions, and Outcomes

It strongly suggested sarcoidosis since tuberculosis, lymphoma, and connective tissue disease were all excluded. Due to severe conditions and multiorgan involvement, we tried to provide methylprednisolone for this patient. After 9 months of oral glucocorticoids therapy, his subjective symptoms as well as hematological and radiological findings were all improved. His leg skin ulceration and scab were also completely disappeared.

Conclusion

Sarcoidosis has diverse clinical presentations, and many patients present with atypical symptoms. It needs to be timely identified by the clinician and carefully differentiated from other diseases with similar findings so as to make an accurate diagnosis. In this case, the patient had a poor clinical response to glucocorticoids in the early stage of treatment due to the severe condition and multi-organ involvement. It is worth noting that the patient had improved significantly after 9 months of treatment of corticosteroids, which suggested that follow-up is critical.
Over-the-Scope Clip Applications as First-Line Therapy in the Treatment of Upper Non-variceal Gastrointestinal Bleeding, Perforations, and Fistulas
Authors: Qiu Jiayu , Xu Jun , Zhang Yanxia , Liao Foqiang , Zhu Zhenhua , Shu Xu , Chen Youxiang , Pan Xiaolin
Published: February 2022

Background

The over-the-scope clip (OTSC) is an innovative device and has been successfully used in endoscopic treatment, however, there is a lack of clinical data from China. The aim of this study is to investigate the OTSC applications in the treatment of upper non-variceal gastrointestinal bleeding (UNVGIB), perforations, and fistulas in China.

Methods

In total, 80 patients were treated with one OTSC respectively as first-line therapy in our endoscopy center between January 2016 and November 2020. Among them, 41 patients had UNVGIB, 34 patients had perforations, and five patients had fistulas. The technical and clinical success rates were used to assess the efficacy of OTSC on the above diseases. In addition, we compared the hemostatic efficacy of OTSC with the standard endoscopic therapy in ulcer bleeding and Dieulafoy's lesion by propensity score matching analysis.

Results

In general, the OTSCs were applied successfully in all patients and achieved 100% (80/80) technical success. The clinical success of all patients was 91.3% (73/80). Among 41 patients with UNVGIB, the clinical success was 85.4% (35/41); 6 patients presented with recurrence. For patients of Dieulafoy's lesion and under antithrombotic therapy, we found that OTSC treatment had both efficient and reliable hemostasis effects. In addition, according to the characteristics of ulcers, site of bleeding lesion, and Blatchford score, all patients received similar and reliable clinical success rates. After propensity score matching, we found that OTSC treatment had low rebleeding rates when compared with standard endoscopic therapy in both Dieulafoy's lesion (15.0 vs 30.0%) and ulcer bleeding (17.6 vs 29.4%). Among 34 patients with perforations, the clinical success was 100% (34/34). Among five patients with fistulas, only one patient failed in maintaining the OTSC before esophageal fistula healing, and the clip achieved an overall clinical success of 80% (4/5).

Conclusion

The OTSC represents a safe and effective endoscopic therapy for UNVGIB, perforations, and fistulas as first-line treatment, especially for Dieulafoy's lesion or patients under antithrombotic therapy for UNVGIB, etc. However, OTSC application in these specific lesions or patients lacks adequate evidence as first-line treatment. Therefore, further larger sample and multi-center clinical trials are required to improve its indications in clinical treatment.
The Improved Catheterization Is Associated With the Deeper Radial Arteries in Ultrasound-Guided Dynamic Needle Tip Positioning Technique
Authors: Tian Yuan , Bai Bing , Zhang Yuelun , Che Lu , Wang Jin , Wang Yi , Yu Chunhua , Huang Yuguang
Published: February 2022

Objective

This study aimed to determine the associations between the first-attempt success and arterial depth in ultrasound-guided radial artery catheterization (RAC) with dynamic needle tip positioning (DNTP) technique. This study also aimed to further explore the cut-off depth correlated to improved first-attempt success catheterization in less time.

Methods

The cases undertaken by RAC within the DNTP technique between March 2019 and July 2020 were extracted from our institutional cohort database. Relevant variables were collected, including patients' demographics and catheterized information. Univariable and multivariable logistic regression analyses were performed to determine the association. The receiver operating characteristic (ROC) curve and the Youden index were used to explore the cut-off values of the arterial depth. Categorized cases according to the cut-off values, the Kaplan-Meier analysis, and the log-rank test were used to determine the difference of first-attempt success with limited catheterized time between groups.

Results

In this study, 119 patients were enrolled and 98 achieved first-attempt success. The first-attempt success catheterization was observed to be correlated to arterial depth (p < 0.01, odds ratio 6.47). An optimal cut-off depth of 2.25 mm was found using the Youden index (0.53) by ROC curve (area under curve 0.77). Arterial depth of more than 2.25 mm was correlated to improved first-attempt success catheterization in less time (log-rank p < 0.01).

Conclusion

To achieve first-attempt success catheterization using the DNTP technique, an arterial depth of more than 2.25 mm was associated with less catheterized time.
Role of Age-Related Changes in DNA Methylation in the Disproportionate Susceptibility and Worse Outcomes of Sepsis in Older Adults
Authors: Lang Xiabing , Shen Lingling , Zhu Tingting , Zhao Wenjun , Chen Yang , Zhu Chaohong , Su Qun , Wang Cuili , Wang Yucheng , Neri Francesco , Jiang Hong , Chen Jianghua
Published: February 2022

Sepsis, a complex multisystem disorder, is among the top causes of hospitalization and mortality in older adults. However, the mechanisms underlying the disproportionate susceptibility to sepsis and worse outcomes in the elderly are not well understood. Recently, changes in DNA methylation have been shown to be linked to aging processes and age-related diseases. Thus, we postulated that age-related changes in DNA methylation may play a role in the onset and prognosis of sepsis in elderly patients. Here, we performed genome-wide methylation profiling of peripheral blood from patients with sepsis and controls. Among the CpG sites whose methylation changes may contribute to an increase in sepsis susceptibility or mortality, 241 sites that possessed age-related changes in DNA methylation in controls may partly explain the increased risk of sepsis in older adults, and 161 sites whose methylation significantly correlated with age in sepsis group may be the potential mechanisms underlying the worse outcomes of elderly septic patients. Finally, an independent cohort was used to validate our findings. Together, our study demonstrates that age-related changes in DNA methylation may explain in part the disproportionate susceptibility and worse outcomes of sepsis in older adults.
Integrative Genomics Sheds Light on Evolutionary Forces Shaping the Acidithiobacillia Class Acidophilic Lifestyle
Authors: González-Rosales Carolina , Vergara Eva , Dopson Mark , Valdés Jorge H. , Holmes David S.
Published: February 2022

Extreme acidophiles thrive in environments rich in protons (pH values <3) and often high levels of dissolved heavy metals. They are distributed across the three domains of the Tree of Life including members of the Proteobacteria. The Acidithiobacillia class is formed by the neutrophilic genus Thermithiobacillus along with the extremely acidophilic genera Fervidacidithiobacillus, Igneacidithiobacillus, Ambacidithiobacillus, and Acidithiobacillus. Phylogenomic reconstruction revealed a division in the Acidithiobacillia class correlating with the different pH optima that suggested that the acidophilic genera evolved from an ancestral neutrophile within the Acidithiobacillia. Genes and mechanisms denominated as “first line of defense” were key to explaining the Acidithiobacillia acidophilic lifestyle including preventing proton influx that allows the cell to maintain a near-neutral cytoplasmic pH and differ from the neutrophilic Acidithiobacillia ancestors that lacked these systems. Additional differences between the neutrophilic and acidophilic Acidithiobacillia included the higher number of gene copies in the acidophilic genera coding for “second line of defense” systems that neutralize and/or expel protons from cell. Gain of genes such as hopanoid biosynthesis involved in membrane stabilization at low pH and the functional redundancy for generating an internal positive membrane potential revealed the transition from neutrophilic properties to a new acidophilic lifestyle by shaping the Acidithiobacillaceae genomic structure. The presence of a pool of accessory genes with functional redundancy provides the opportunity to “hedge bet” in rapidly changing acidic environments. Although a core of mechanisms for acid resistance was inherited vertically from an inferred neutrophilic ancestor, the majority of mechanisms, especially those potentially involved in resistance to extremely low pH, were obtained from other extreme acidophiles by horizontal gene transfer (HGT) events.
Role of Dexamethasone and Methylprednisolone Corticosteroids in Coronavirus Disease 2019 Hospitalized Patients: A Review
Authors: Mehta Jyoti , Rolta Rajan , Mehta Brij Bhushan , Kaushik Neha , Choi Eun Ha , Kaushik Nagendra Kumar
Published: February 2022

The WHO announced coronavirus disease 2019 (COVID-19) as a pandemic disease globally on March 11, 2020, after it emerged in China. The emergence of COVID-19 has lasted over a year, and despite promising vaccine reports that have been produced, we still have a long way to go until such remedies are accessible to everyone. The immunomodulatory strategy has been kept at the top priority for the research agenda for COVID-19. Corticosteroids have been used to modulate the immune response in a wide range of diseases for the last 70 years. These drugs have been shown to avoid and reduce inflammation in tissues and the bloodstream through non-genomic and genomic effects. Now, the use of corticosteroids increased the chance of survival and relief by combating the viral strong inflammatory impacts and has moved to the forefront in the management of patients seeking supplemental oxygen. The goal of this review is to illuminate dexamethasone and methylprednisolone, i.e., in terms of their chemical and physical properties, role in COVID-19 patients suffering from pneumonia, the proposed mode of action in COVID-19, pharmacokinetics, pharmacodynamics, clinical outcomes in immunocompromised populations with COVID-19, interaction with other drugs, and contradiction to explore the trends and perspectives for future research. Literature was searched from scientific databases such as Science Direct, Wiley, Springer, PubMed, and books for the preparation of this review. The RECOVERY trial, a massive, multidisciplinary, randomized, and open-label trial, is mainly accountable for recommendations over the usage of corticosteroids in COVID-19 patients. The corticosteroids such as dexamethasone and methylprednisolone in the form of medication have anti-inflammatory, analgesic, and anti-allergic characteristics, including the ability to inhibit the immune system. These drugs are also recommended for treating symptoms of multiple ailments such as rheumatic and autoimmune diseases, leukemia, multiple myeloma, and Hodgkin’s and non-Hodgkin’s lymphoma along with other drugs. Toxicology studies proved them safe usually at low dosage via oral or other routes.
Six Months of Piano Training in Healthy Elderly Stabilizes White Matter Microstructure in the Fornix, Compared to an Active Control Group
Authors: Jünemann Kristin , Marie Damien , Worschech Florian , Scholz Daniel S. , Grouiller Frédéric , Kliegel Matthias , Van De Ville Dimitri , James Clara E. , Krüger Tillmann H. C. , Altenmüller Eckart , Sinke Christopher
Published: February 2022

While aging is characterized by neurodegeneration, musical training is associated with experience-driven brain plasticity and protection against age-related cognitive decline. However, evidence for the positive effects of musical training mostly comes from cross-sectional studies while randomized controlled trials with larger sample sizes are rare. The current study compares the influence of six months of piano training with music listening/musical culture lessons in 121 musically naïve healthy elderly individuals with regard to white matter properties using fixel-based analysis. Analyses revealed a significant fiber density decline in the music listening/musical culture group (but not in the piano group), after six months, in the fornix, which is a white matter tract that naturally declines with age. In addition, these changes in fiber density positively correlated to episodic memory task performances and the amount of weekly piano training. These findings not only provide further evidence for the involvement of the fornix in episodic memory encoding but also more importantly show that learning to play the piano at an advanced age may stabilize white matter microstructure of the fornix.
Modulation of Gq/PLC-Mediated Signaling by Acute Lithium Exposure
Authors: Sánchez Triviño Cesar Adolfo , Landinez Maria Paula , Duran Sara , Gomez María del Pilar , Nasi Enrico
Published: February 2022

Although lithium has long been one of the most widely used pharmacological agents in psychiatry, its mechanisms of action at the cellular and molecular levels remain poorly understood. One of the targets of Li+ is the phosphoinositide pathway, but whereas the impact of Li+ on inositol lipid metabolism is well documented, information on physiological effects at the cellular level is lacking. We examined in two mammalian cell lines the effect of acute Li+ exposure on the mobilization of internal Ca2+ and phospholipase C (PLC)-dependent membrane conductances. We first corroborated by Western blots and immunofluorescence in HEK293 cells the presence of key signaling elements of a muscarinic PLC pathway (M1AchR, Gq, PLC-β1, and IP3Rs). Stimulation with carbachol evoked a dose-dependent mobilization of Ca, as determined with fluorescent indicators. This was due to release from internal stores and proved susceptible to the PLC antagonist U73122. Li+ exposure reproducibly potentiated the Ca response in a concentration-dependent manner extending to the low millimolar range. To broaden those observations to a neuronal context and probe potential Li modulation of electrical signaling, we next examined the cell line SHsy5y. We replicated the potentiating effects of Li on the mobilization of internal Ca, and, after characterizing the basic properties of the electrical response to cholinergic stimulation, we also demonstrated an equally robust upregulation of muscarinic membrane currents. Finally, by directly stimulating the signaling pathway at different links downstream of the receptor, the site of action of the observed Li effects could be narrowed down to the G protein and its interaction with PLC-β. These observations document a modulation of Gq/PLC/IP3-mediated signaling by acute exposure to lithium, reflected in distinct physiological changes in cellular responses.
New Remote Cerebral Microbleeds on T2*-Weighted Echo Planar MRI After Intravenous Thrombolysis for Acute Ischemic Stroke
Authors: Jabłoński Bartosz , Gójska-Grymajło Anna , Ossowska Daria , Szurowska Edyta , Wyszomirski Adam , Rojek Bartłomiej , Karaszewski Bartosz
Published: February 2022

Background

The main and well-defined complication of intravenous administration of recombinant tissue plasminogen activator (tPA) in patients with acute ischemic stroke (AIS) is symptomatic intracranial hemorrhage (sICH). However, rtPA might also be connected with the formation of cerebral microbleeds (CMBs), located remotely from the ischemic lesions, that may remain clinically silent. This association might be important because the load of CMBs has been associated with cognitive impairment. We investigated whether administration of rtPA in AIS results in the appearance of new CMBs and if the initial load of CMBs is associated with hemorrhagic transformation.

Methods

A total of fifty-nine consecutive patients with AIS treated with rtPA underwent MRI including T2*-weighted Echo Planar Imaging (T2*-EPI) shortly before and 7–9 days after rtPA administration. We calculated the load of new CMBs located outside the MR diffusion restriction area in the follow-up imaging and assessed hemorrhagic transformation with ECASS-II scoring.

Results

A total of forty-nine patients were included for the final analysis. On initial T2*-EPI-GRE, 37 baseline microbleeds (CMBs) were observed in 14 patients (28.6%). On follow-up T2*-EPI-GRE amount of CMBs increased to a total number of 103. New CMBs were found in 5 (14.3%) of 35 patients without and in 9 (64.3%) of 14 with any baseline CMBs. Multiple logistic regression analysis indicated that presence of baseline CMBs (risk ratio [RR] 5.95, 95% CI 2.69–13.20, p < 0.001) and lower platelets level (risk ratio [RR] 0.992, 95% CI 0.986–0.998, p = 0.007) were independently associated with new CMBs. The baseline load of CMBs was not associated with the risk of hemorrhagic transformation.

Conclusion

In this study, new CMBs were found in nearly 30% of patients with AIS on the 7–9 days after rtPA treatment. Baseline CMBs correlated with a higher risk of new CMBs appearing after the rtPA treatment, independently of other factors. At the same time, in our sample, baseline CMBs did not correlate with an increased risk of hemorrhagic transformation. Since the associations between the CMBs load and cognitive impairment have already been proved, further studies are warranted to investigate possible associations between the thrombolytic treatment of patients with AIS, mainly those with baseline CMBs, and the risk of earlier cognitive decline.
Co-occurrence of Fatigue and Depression in People With Multiple Sclerosis: A Mini-Review
Authors: Tarasiuk Joanna , Kapica-Topczewska Katarzyna , Czarnowska Agata , Chorąży Monika , Kochanowicz Jan , Kułakowska Alina
Published: February 2022

Fatigue and depression are common conditions diagnosed in people with multiple sclerosis (MS). Fatigue defined as subjective lack of physical and/or mental energy is present in 35–97% of people with MS, who classify it as one of the most serious symptoms interfering with daily activities and influencing the quality of life. Depression is diagnosed in about 50% of people with MS. Since fatigue and depression frequently coexists, it may be quite hard to differentiate them. Primary fatigue and primary depression in MS are caused by inflammatory, oxidative/nitrosative, and neurodegenerative processes leading to demyelination, axonal damage, and brain atrophy. In people with MS and comorbid fatigue and/or depression there is reported increased serum and cerebrospinal fluid concentration of inflammatory mediators such as tumor necrosis factor, interleukins (IL-1a, IL-1b, IL-6), interferon γ and neopterin. Moreover, the brain atrophy of prefrontal, frontal, parietotemporal regions, thalamus, and basal ganglia was observed in people with MS with fatigue and/or depression. The secondary fatigue and secondary depression in people with MS may be caused by emotional factors, sleep disorders, pain, the coexistence of other diseases, and the use of medications. In some studies, the use of disease-modifying therapies positively influenced fatigue, probably by reducing the inflammatory response, which proves that fatigue and depression are closely related to immunological factors. In this mini-review, the pathogenesis, methods of evaluation and differentiation, and possible therapies for fatigue and depression in MS are discussed.
Multimodal Evidence of Atypical Processing of Eye Gaze and Facial Emotion in Children With Autistic Traits
Authors: Bagherzadeh-Azbari Shadi , Lau Gilbert Ka Bo , Ouyang Guang , Zhou Changsong , Hildebrandt Andrea , Sommer Werner , Lui Ming
Published: February 2022

According to the shared signal hypothesis (SSH) the impact of facial expressions on emotion processing partially depends on whether the gaze is directed toward or away from the observer. In autism spectrum disorder (ASD) several aspects of face processing have been found to be atypical, including attention to eye gaze and the identification of emotional expressions. However, there is little research on how gaze direction affects emotional expression processing in typically developing (TD) individuals and in those with ASD. This question is investigated here in two multimodal experiments. Experiment 1 required processing eye gaze direction while faces differed in emotional expression. Forty-seven children (aged 9–12 years) participated. Their Autism Diagnostic Observation Schedule (ADOS) scores ranged from 0 to 6 in the experiment. Event-related potentials (ERPs) were sensitive to gaze direction and emotion, but emotion processing did not depend on gaze direction. However, for angry faces the gaze direction effect on the N170 amplitude, as typically observed in TD individuals, diminished with increasing ADOS score. For neutral expressions this correlation was not significant. Experiment 2 required explicit emotion classifications in a facial emotion composite task while eye gaze was manipulated incidentally. A group of 22 children with ASD was compared to a propensity score-matched group of TD children (mean age = 13 years). The same comparison was carried out for a subgroup of nine children with ASD who were less trained in social cognition, according to clinician’s report. The ASD group performed overall worse in emotion recognition than the TD group, independently of emotion or gaze direction. However, for disgust expressions, eye tracking data revealed that TD children fixated relatively longer on the eyes of the stimulus face with a direct gaze as compared with averted gaze. In children with ASD we observed no such modulation of fixation behavior as a function of gaze direction. Overall, the present findings from ERPs and eye tracking confirm the hypothesis of an impaired sensitivity to gaze direction in children with ASD or elevated autistic traits, at least for specific emotions. Therefore, we conclude that multimodal investigations of the interaction between emotional processing and stimulus gaze direction are promising to understand the characteristics of individuals differing along the autism trait dimension.
ProbeInterface: A Unified Framework for Probe Handling in Extracellular Electrophysiology
Authors: Garcia Samuel , Sprenger Julia , Holtzman Tahl , Buccino Alessio P.
Published: February 2022

Recording neuronal activity with penetrating extracellular multi-channel electrode arrays, more commonly known as neural probes, is one of the most widespread approaches to probe neuronal activity. Despite a plethora of available extracellular probe designs, the time-consuming process of mapping of electrode channel order and relative geometries, as required by spike-sorting software is invariably left to the end-user. Consequently, this manual process is prone to mis-mapping mistakes, which in turn lead to undesirable spike-sorting errors and inefficiencies. Here, we introduce ProbeInterface, an open-source project that aims to unify neural probe metadata descriptions by removing the manual step of probe mapping prior to spike-sorting for the analysis of extracellular neural recordings. ProbeInterface is first of all a Python API, which enables users to create and visualize probes and probe groups at any required complexity level. Second, ProbeInterface facilitates the generation of comprehensive wiring description in a reproducible fashion for any specific data-acquisition setup, which usually involves the use of a recording probe, a headstage, adapters, and an acquisition system. Third, we collaborate with probe manufacturers to compile an open library of available probes, which can be downloaded at run time using our Python API. Finally, with ProbeInterface we define a file format for probe handling which includes all necessary information for a FAIR probe description and is compatible with and complementary to other open standards in neuroscience.