bluuebunny/crossref_metadata_2025 huggingface dataset:
TRADISI NGELEGI MARGA DALAM MASYARAKAT KARO: PROBLEMA IDENTITAS INTEGRASI ATAU MULTIKULTUR (The Tradition of Ngelegi Marga in Karo Society: The Problem of Integrated or Multicultural Identity)
Authors: Sembiring Raharja , Butar butar Rut Debora
Published: March 2021

This article aims to describe and to explain the tradition of ngelegi marga in Karo society. It is intended to answer the problem of integrated or multicultural identity due to this tradition. The tradition of ngelegi merga or beru (picking up clans) is a cultural solution for the Karo people to respond to the increasingly complex interactions and expansion of Karo community. This tradition often generates a dilemma between Integration and multiculturalism. The research used in this paper is ethnographic and phenomonological studies, data was obtained through participatory observation, interview and literature study. The tradition of ngelegi merga or trying to embrace all people becomes the subject in the community, so that there is no other subject. The tradition of ngelegi merga or beru does not ignore initial identities but the way of living and establishing relationship within the Karo community.

Keywords: Integration, Karo, multicultural, Ngelegi merga or beru.
Comparing the effect of insulin infusion alone and in combination of insulin infusion with salbutamol nebulization in treatment of hyperkalemia in diabetic and non-diabetic patients
Authors: TIWARI Rohit , NAIN Parmınder , KAUR Jasmine , RAO Harbir , KAUR Jaspreet
Published: March 2021

Objective: To evaluate the clinical efficacy and comparison of potassium lowering effect of insulin infusion alone and insulin infusion with salbutamol nebulization.
Methods: This interventional study was conducted in a tertiary care hospital, for a period of one year. A total of 190 patients with hyperkalemia were divided into two groups. Group-A (diabetic [D] and non-diabetic [ND] patients) received salbutamol 20 mg three times daily (TDS) (nebulizer 5mg/2.5mL) administered over a period of 15 minutes with 10 units of regular insulin (diluted with 25% dextrose in non-diabetic only) over 30 minute TDS via infusion. Group-B (diabetic and non-diabetic patients) received 10 units of regular insulin (diluted with 25% dextrose in non-diabetic patients only) administered over 30 minute TDS via infusion. Potassium and glucose level was measured in patient blood sample after 0, 6, 12 and 24 hrs of treatment.
Results: The potassium level was decreased by 30.09% (D) and 31.98% (ND) in Group-A, whereas by 31.98% (D) and 20.49% (ND) in Group-B, after 24 hrs. Whereas blood glucose level in diabetic patients of Group-A and Group-B was found to decrease up to 28.85 % and 40.78 % respectively after 6 hours. Both the treatments were found to be effective without any complication i.e. hypoglycaemia and hypokalaemia. Moreover, renal, liver, cardiac and respiratory function test also did not show significant changes after treatments when recorded bihourly
Conclusion: From the results, salbutamol nebulizer with insulin is more effective in the treatment of hyperkalemia in diabetic and non-diabetic patients.
Short-Term Impact of Point-Source Enrichment on the Behavior of Gestating Sows Housed in Groups
Authors: Zhitnitskiy Perle E. , Terreaux Claire M. H. A. , Phillips Hannah N. , Ventura Beth A.
Published: March 2021

Environmental enrichment is an important strategy to improve the welfare of farm animals. However, relatively little is known about enrichment for gestating sows, especially those raised on farms with slatted floors and for which provision of straw may be difficult. The objective of this study was therefore to investigate the short-term (4 d) impact of a point-source enrichment object on the behavior of gestating sows housed in group pens. Four pens of gestating sows on a university research farm were randomly allocated to receive either enrichment or no enrichment (control) in a 2 by 2 crossover design. Time budgets were established by video recording focal sows' behaviors (n= 10 focals per pen) every 15 min between 0800 and 1500 every day. Enrichment use was further characterized by continuous behavior sampling for a 1 h interval between 0830 and 0930 each day. The impact of parity, lameness and presence of stereotypical behavior such as sham chewing on enrichment use was evaluated. Over the course of the study, focal sows spent approximately 73% of observations inactive [either lying down (70%), standing (2%), or sitting (1%)]. Within the remaining observations, sows were most commonly observed sham-chewing (16%), followed by 3% exploring, 2% feeding, 2% walking and 1% interacting with the enrichment when it was available. Low-parity sows, moderately-lame sows, and sows observed sham chewing at baseline displayed more consistent enrichment use over the course of the study (p= 0.02,p< 0.01,p= 0.04, respectively). While no adverse behavioral effects (increased agonism or sham chewing) due to provision or removal of the enrichment object were observed and while 85% of sows were observed to interact with enrichment at least once, interest declined sharply after the first day. We conclude that further research is needed to identify effective and sustainable enrichment strategies for gestating sows.
Approaches to Improve Endometrial Receptivity in Case of Repeated Implantation Failures
Authors: Makrigiannakis Antonis , Makrygiannakis Fanourios , Vrekoussis Thomas
Published: March 2021

Repeated implantation failures are a constant challenge in reproductive medicine with a significant impact both on health providers and on infertile couples. Several approaches have been proposed so far as effective; however, accumulative data have clarified that most of the treatment options do not have the evidence base for a generalized application to be suggested by the relevant societies. Implantation failures are attributed to either poor quality embryos or to defected endometrial receptivity. The current review aims to summarize in a systematic way all the new trends in managing RIF via interference with endometrial receptivity. The authors focus mainly, but not exclusively, on endometrial injury prior to embryo transfer and endometrial priming with autologous cells or biological agents. To this direction, a systematic search of the Pubmed database has been conducted taking into account the emerged evidence of the last two decades. All the suggested interventions are herein presented and analyzed in terms of reproductive outcomes. It is evident that properly powered and designed randomized trials are needed to support a new standard approach in RIF treatment that will safely be incorporated in national and international guidelines.
Transcriptome and DNA Methylation Profiles of Mouse Fetus and Placenta Generated by Round Spermatid Injection
Authors: Zhu Haibo , Sun Hao , Yu Dawei , Li Tianda , Hai Tang , Liu Chao , Zhang Ying , Chen Yurong , Dai Xiangpeng , Li Ziyi , Li Wei , Liu Ruizhi , Feng Guihai , Zhou Qi
Published: March 2021

Low birth efficiency and developmental abnormalities in embryos derived using round spermatid injection (ROSI) limit the clinical application of this method. Further, the underlying molecular mechanisms remain elusive and warrant further in-depth study. In this study, the embryonic day (E) 11.5 mouse fetuses and corresponding placentas derived upon using ROSI, intracytoplasmic sperm injection (ICSI), and naturalin vivofertilized (control) embryos were collected. Transcriptome and DNA methylation profiles were analyzed and compared using RNA-sequencing (RNA-seq) and whole-genome bisulfite sequencing, respectively. RNA-seq results revealed similar gene expression profiles in the ROSI, ICSI, and control fetuses and placentas. Compared with the other two groups, seven differentially expressed genes (DEGs) were identified in ROSI fetuses, and ten DEGs were identified in the corresponding placentas. However, no differences in CpG methylation were observed in fetuses and placentas from the three groups. Imprinting control region methylation and imprinted gene expression were the same between the three fetus and placenta groups. Although 49 repetitive DNA sequences (RS) were abnormally activated in ROSI fetuses, RS DNA methylation did not differ between the three groups. Interestingly, abnormal hypermethylation in promoter regions and low expression ofFggyandRec8were correlated with a crown-rump length less than 6 mm in one ROSI fetus. Our study demonstrates that the transcriptome and DNA methylation in ROSI-derived E11.5 mouse fetuses and placentas were comparable with those in the other two groups. However, some abnormally expressed genes in the ROSI fetus and placenta warrant further investigation to elucidate their effect on the development of ROSI-derived embryos.
A Metabolomics and Molecular Networking Approach to Elucidate the Structures of Secondary Metabolites Produced by Serratia marcescens Strains
Authors: Clements Tanya , Rautenbach Marina , Ndlovu Thando , Khan Sehaam , Khan Wesaal
Published: March 2021

An integrated approach that combines reverse-phase high-performance liquid chromatography (RP-HPLC), electrospray ionization mass spectrometry, untargeted ultra-performance liquid chromatography coupled to tandem mass spectrometry (UPLC-MSE) and molecular networking (using the Global Natural Products Social molecular network platform) was used to elucidate the metabolic profiles and chemical structures of the secondary metabolites produced by pigmented (P1) and non-pigmented (NP1) Serratia marcescens (S. marcescens) strains. Tandem mass spectrometry-based molecular networking guided the structural elucidation of 18 compounds for the P1 strain (including 6 serratamolides, 10 glucosamine derivatives, prodigiosin and serratiochelin A) and 15 compounds for the NP1 strain (including 8 serratamolides, 6 glucosamine derivatives and serratiochelin A) using the MSE fragmentation profiles. The serratamolide homologues were comprised of a peptide moiety of two L-serine residues (cyclic or open-ring) linked to two fatty acid chains (lengths of C10, C12, or C12:1). Moreover, the putative structure of a novel open-ring serratamolide homologue was described. The glucosamine derivative homologues (i.e., N-butylglucosamine ester derivatives) consisted of four residues, including glucose/hexose, valine, a fatty acid chain (lengths of C13 – C17 and varying from saturated to unsaturated) and butyric acid. The putative structures of seven novel glucosamine derivative homologues and one glucosamine derivative congener (containing an oxo-hexanoic acid residue instead of a butyric acid residue) were described. Moreover, seven fractions collected during RP-HPLC, with major molecular ions corresponding to prodigiosin, serratamolides (A, B, and C), and glucosamine derivatives (A, C, and E), displayed antimicrobial activity against a clinical Enterococcus faecalis S1 strain using the disc diffusion assay. The minimum inhibitory and bactericidal concentration assays however, revealed that prodigiosin exhibited the greatest antimicrobial potency, followed by glucosamine derivative A and then the serratamolides (A, B, and C). These results provide crucial insight into the secondary metabolic profiles of pigmented and non-pigmented S. marcescens strains and confirms that S. marcescens strains are a promising natural source of novel antimicrobial metabolites.
β2 Integrin-Mediated Susceptibility to Paracoccidioides brasiliensis Experimental Infection in Mice
Authors: de Oliveira Stephan Alberto Machado , Reis Janayna Nunes , Catão Elisa , Amaral Andre Correa , Souza Ana Camila Oliveira , Ribeiro Alice Melo , Faccioli Lúcia Helena , Carneiro Fabiana Pirani , Marina Clara Luna Freitas , Bürgel Pedro Henrique , Fernandes Larissa , Tavares Aldo Henrique , Bocca Anamelia Lorenzetti
Published: March 2021

The earliest interaction between macrophages andParacoccidioides brasiliensisis particularly important in paracoccidioidomycosis (PCM) progression, and surface proteins play a central role in this process. The present study investigated the contribution of β2 integrin inP. brasiliensis-macrophage interaction and PCM progression. We infected β2-low expression (CD18low) and wild type (WT) mice withP. brasiliensis18. Disease progression was evaluated for fungal burden, lung granulomatous lesions, nitrate levels, and serum antibody production. Besides, thein vitrocapacity of macrophages to internalize and kill fungal yeasts was investigated. Our results revealed that CD18lowmice infected with Pb18 survived during the time analyzed; their lungs showed fewer granulomas, a lower fungal load, lower levels of nitrate, and production of high levels of IgG1 in comparison to WT animals. Our results revealed thatin vitromacrophages from CD18lowmice slowly internalized yeast cells, showing a lower fungal burden compared to WT cells. The migration capacity of macrophages was compromised and showed a higher intensity in the lysosome signal when compared with WT mice. Our data suggest that β2 integrins play an important role in fungal survival inside macrophages, and once phagocytosed, the macrophage may serve as a protective environment forP. brasiliensis.
Understanding Metabolic Regulation Between Host and Pathogens: New Opportunities for the Development of Improved Therapeutic Strategies Against Mycobacterium tuberculosis Infection
Authors: Park Ji-Hae , Shim Dahee , Kim Keu Eun San , Lee Wonsik , Shin Sung Jae
Published: March 2021

Mycobacterium tuberculosis (Mtb) causes chronic granulomatous lung disease in humans. Recently, novel strategies such as host-directed therapeutics and adjunctive therapies that enhance the effect of existing antibiotics have emerged to better control Mtb infection. Recent advances in understanding the metabolic interplay between host immune cells and pathogens have provided new insights into how their interactions ultimately influence disease outcomes and antibiotic-treatment efficacy. In this review, we describe how metabolic cascades in immune environments and relevant metabolites produced from immune cells during Mtb infection play critical roles in the progression of diseases and induction of anti-Mtb protective immunity. In addition, we introduce how metabolic alterations in Mtb itself can lead to the development of persister cells that are resistant to host immunity and can eventually evade antibiotic attacks. Further understanding of the metabolic link between host cells and Mtb may contribute to not only the prevention of Mtb persister development but also the optimization of host anti-Mtb immunity together with enhanced efficacy of existing antibiotics. Overall, this review highlights novel approaches to improve and develop host-mediated therapeutic strategies against Mtb infection by restoring and switching pathogen-favoring metabolic conditions with host-favoring conditions.
Covid-19 Discourse on Twitter: How the Topics, Sentiments, Subjectivity, and Figurative Frames Changed Over Time
Authors: Wicke Philipp , Bolognesi Marianna M.
Published: March 2021

The words we use to talk about the current epidemiological crisis on social media can inform us on how we are conceptualizing the pandemic and how we are reacting to its development. This paper provides an extensive explorative analysis of how the discourse about Covid-19 reported on Twitter changes through time, focusing on the first wave of this pandemic. Based on an extensive corpus of tweets (produced between 20th March and 1st July 2020) first we show how the topics associated with the development of the pandemic changed through time, using topic modeling. Second, we show how the sentiment polarity of the language used in the tweets changed from a relatively positive valence during the first lockdown, toward a more negative valence in correspondence with the reopening. Third we show how the average subjectivity of the tweets increased linearly and fourth, how the popular and frequently used figurative frame of WAR changed when real riots and fights entered the discourse.
Proinflammatory Cytokine Modulates Intracellular Calcium Handling and Enhances Ventricular Arrhythmia Susceptibility
Authors: Tsai Yung-Nan , Hsiao Ya-Wen , Lin Shien-Fong , Chan Yi-Hsin , Hsieh Yu-Cheng , Tang Wei-Hua , Lee An-Sheng , Huang Yu-Ting , Li Hsing-Yuan , Chao Tze-Fan , Higa Satoshi , Wu Tsu-Juey , Chang Shih-Lin , Chen Shih-Ann
Published: March 2021

Background: The mechanism of Interleukin-17 (IL-17) induced ventricular arrhythmia (VA) remains unclear. This study aimed to investigate the effect of intracellular calcium (Cai) handling and VA susceptibility by IL-17.

Methods: The electrophysiological properties of isolated perfused rabbit hearts under IL-17 (20 ng/ml, N = 6) and the IL-17 with neutralizer (0.4 μg/ml, N = 6) were evaluated using an optical mapping system. The action potential duration (APD) and Cai transient duration (CaiTD) were examined, and semiquantitative reverse transcriptase-polymerase chain reaction analysis of ion channels was performed.

Results: There were longer APD80, CaiTD80 and increased thresholds of APD and CaiTD alternans, the maximum slope of APD restitution and induction of VA threshold in IL-17 group compared with those in IL-17 neutralizer and baseline groups. During ventricular fibrillation, the number of phase singularities and dominant frequency were both significantly greater in IL-17 group than in baseline group. The mRNA expressions of the Na+/Ca2+ exchanger, phospholamban, and ryanodine receptor Ca2+ release channel were upregulated, and the subunit of L-type Ca2+ current and sarcoplasmic reticulum Ca2+-ATPase 2a were significantly reduced in IL-17 group compared to baseline and IL-17 neutralizer group.

Conclusions: IL-17 enhanced CaiTD and APD alternans through disturbances in calcium handling, which may increase VA susceptibility.
Validation and Feasibility of Echocardiographic Assessment of Systemic Right Ventricular Function: Serial Correlation With MRI
Authors: Zandstra Tjitske E. , Jongbloed Monique R. M. , Widya Ralph L. , ten Harkel Arend D. J. , Holman Eduard R. , Mertens Bart J. A. , Vliegen Hubert W. , Egorova Anastasia D. , Schalij Martin J. , Kiès Philippine
Published: March 2021

Background: Inherent to its geometry, echocardiographic imaging of the systemic right ventricle (RV) is challenging. Therefore, echocardiographic assessment of systemic RV function may not always be feasible and/or reproducible in daily practice. Here, we aim to validate the usefulness of a comprehensive range of 32 echocardiographic measurements of systemic RV function in a longitudinal cohort by serial assessment of their correlations with cardiac magnetic resonance (CMR)-derived systemic RV ejection fraction (RVEF).

Methods: A single-center, retrospective cohort study was performed. Adult patients with a systemic RV who underwent a combination of both CMR and echocardiography at two different points in time were included. Off-line analysis of echocardiographic images was blinded to off-line CMR analysis and vice versa. In half of the echocardiograms, measurements were repeated by a second observer blinded to the results of the first. Correlations between echocardiographic and CMR measures were assessed with Pearson's correlation coefficient and interobserver agreement was quantified with intraclass correlation coefficients (ICC).

Results: Fourteen patients were included, of which 4 had congenitally corrected transposition of the great arteries (ccTGA) and 10 patients had TGA late after an atrial switch operation. Eight patients (57%) were female. There was a mean of 8 years between the first and second imaging assessment. Only global systemic RV function, fractional area change (FAC), and global longitudinal strain (GLS) were consistently, i.e., at both time points, correlated with CMR-RVEF (global RV function: r = −0.77/r = −0.63; FAC: r = 0.79/r = 0.67; GLS: r = −0.73/r = −0.70, all p-values < 0.05). The ICC of GLS (0.82 at t = 1, p = 0.006, 0.77 at t = 2, p = 0.024) was higher than the ICC of FAC (0.35 at t = 1, p = 0.196, 0.70 at t = 2, p = 0.051) at both time points.

Conclusion: GLS appears to be the most robust echocardiographic measurement of systemic RV function with good correlation with CMR-RVEF and reproducibility.
Aldosterone-Regulating Receptors and Aldosterone-Driver Somatic Mutations
Authors: Lim Jung Soo , Plaska Samuel W. , Rege Juilee , Rainey William E. , Turcu Adina F.
Published: March 2021

Background

Somatic gene mutations that facilitate inappropriate intracellular calcium entrance have been identified in most aldosterone-producing adenomas (APAs). Studies suggest that angiotensin II and adrenocorticotropic hormone (ACTH) augment aldosterone production from APAs. Little is known, however, regarding possible variations in response to hormonal stimuli between APAs with different aldosterone-driver mutations.

Objective

To analyze the transcript expression of type 1 angiotensin II receptors (AGTR1), ACTH receptors (MC2R), and melanocortin 2 receptor accessory protein (MRAP) in APAs with known aldosterone-driver somatic mutations.

Methods

RNA was isolated from APAs with mutations in: KCNJ5 (n = 14), ATP1A1 (n = 14), CACNA1D (n = 14), and ATP2B3 (n = 5), and from normal adjacent adrenal tissue (n = 45). Transcript expression of MC2R, MRAP, AGTR1, aldosterone synthase (CYP11B2), 17α-hydroxylase/17,20-lyase (CYP17A1), and 11β-hydroxylase (CYP11B1) were quantified using quantitative RT-PCR and normalized to β-actin.

Results

Compared to adjacent normal adrenal tissue, APAs had higher transcript levels of CYP11B2 (2,216.4 [1,112.0, 2,813.5]-fold, p < 0.001), MC2R (2.88 [2.00, 4.52]-fold, p < 0.001), and AGTR1 (1.80 [1.02, 2.80]-fold, p < 0.001]), and lower transcript levels of MRAP, CYP17A1, and CYP11B1 (0.28–0.36, p < 0.001 for all). MC2R and CYP11B2 transcripts were lower in APAs with KCNJ5 vs. other mutations (p < 0.01 for both). MC2R expression correlated positively with that of AGTR1 in APAs harboring KCNJ5 and CACNA1D mutations, and with MRAP expression in APAs harboring ATPase mutations.

Conclusions

While MC2R and AGTR1 are expressed in all APAs, differences were observed based on the underlying aldosterone-driver somatic mutations. In tandem, our findings suggest that APAs with ATPase-mutations are more responsive to ACTH than KCNJ5-mutated APAs.
Con- and Heterospecific Shoaling Makes Invasive Guppies More Risk Taking
Authors: Santiago-Arellano Abigail , Palomera-Hernandez Vianey , Camacho-Cervantes Morelia
Published: March 2021

Invasive species are one of the greatest threats to biodiversity. Behavioral traits are recognized as key to promote individual’s survival in changing conditions. For social species being part of a group is key to carry out vital activities. Heterospecific social environments could provide exotic species with the opportunity to join groups and gain the advantages of being part of a larger population. Short latency to exit a refuge is a behavioral response that could be linked to invasion success as it increases the chances of individuals to locate food sources and other resources in novel environments. The guppy(Poecilia reticulata), a successful invader, has been found to take advantage of the presence of native species to reduce its refuge emergence latency and acquire information. The research was carried out in Mexico, we investigated the effect of heterospecific social contexts that include natives and other invasive viviparous fishes on guppies’ refuge emergence latency. We found that guppies’ emergence latency was shorter when accompanied by another guppy than when alone. Their latency was also shorter when with other invaders and when with native goodeids, but with one of the invaders (Pseudoxiphophorus bimaculatus) and with goodeids (Skiffia bilineata) latency reduction was not as high as when with conspecifics or with the invaderPoecilia gracilis. Our experiment supports both the idea that already established invaders could provide benefits to new ones, and that native species also provide benefits but less than invaders. Increasing our knowledge about conspecific and heterospecific social interactions that could make an exotic species become invasive is key to assess the invasion risk of a community.
Living Things Are Not (20th Century) Machines: Updating Mechanism Metaphors in Light of the Modern Science of Machine Behavior
Authors: Bongard Joshua , Levin Michael
Published: March 2021

One of the most useful metaphors for driving scientific and engineering progress has been that of the “machine.” Much controversy exists about the applicability of this concept in the life sciences. Advances in molecular biology have revealed numerous design principles that can be harnessed to understand cells from an engineering perspective, and build novel devices to rationally exploit the laws of chemistry, physics, and computation. At the same time, organicists point to the many unique features of life, especially at larger scales of organization, which have resisted decomposition analysis and artificial implementation. Here, we argue that much of this debate has focused on inessential aspects of machines – classical properties which have been surpassed by advances in modern Machine Behavior and no longer apply. This emerging multidisciplinary field, at the interface of artificial life, machine learning, and synthetic bioengineering, is highlighting the inadequacy of existing definitions. Key terms such as machine, robot, program, software, evolved, designed, etc., need to be revised in light of technological and theoretical advances that have moved past the dated philosophical conceptions that have limited our understanding of both evolved and designed systems. Moving beyond contingent aspects of historical and current machines will enable conceptual tools that embrace inevitable advances in synthetic and hybrid bioengineering and computer science, toward a framework that identifies essential distinctions between fundamental concepts of devices and living agents. Progress in both theory and practical applications requires the establishment of a novel conception of “machines as they could be,” based on the profound lessons of biology at all scales. We sketch a perspective that acknowledges the remarkable, unique aspects of life to help re-define key terms, and identify deep, essential features of concepts for a future in which sharp boundaries between evolved and designed systems will not exist.
Functional Studies of Novel FOXL2 Variants in Chinese Families With Blepharophimosis–Ptosis–Epicanthus Inversus Syndrome
Authors: Li Fang , Chen Huifang , Wang Yefei , Yang Jie , Zhou Yixiong , Song Xin , Fan Jiayan
Published: March 2021

The blepharophimosis–ptosis–epicanthus inversus syndrome (BPES) is a rare autosomal dominant disease mainly caused by FOXL2 variants. This genetic disorder is usually characterized by eyelid malformation and ovarian dysfunction. However, no reliable genotype/phenotype correlations have been established considering the ovarian phenotype. Here, we detected 15 FOXL2 variants including nine novel ones from 7 families and 8 sporadic cases, which expanded the spectrum of FOXL2 variants and identified a potential clinical cause. Functional studies, with respect to the effect of FOXL2 on the StAR promoter, showed that non-sense variants that lead to protein truncation before the polyalanine tract and missense variants [c.307C > T; p.(Arg103Cys), c.311A > C; p.(His104Pro), c.320G > A; p.(Ser107Asn), and c.335T > A; p.(Phe112Tyr)] within the central portion of the FOXL2 forkhead domain significantly affect its suppressor activity. Such changes may explain the mechanism underlying a more severe phenotype, more likely to result in BPES type I. Furthermore, the missenses variants c.307C > T; p.(Arg103Cys), c.311A > C; p.(His104Pro), and c.320G > A; p.(Ser107Asn) were not able to transactivate OSR2, which is consistent with the eyelid malformation in these patients. The results from our cohort have expanded the spectrum of FOXL2 variants and have provided insights into genotype/phenotype correlations.
The Role of Mitonuclear Incompatibility in Bipolar Disorder Susceptibility and Resilience Against Environmental Stressors
Authors: Gonzalez Suzanne
Published: March 2021

It has been postulated that mitochondrial dysfunction has a significant role in the underlying pathophysiology of bipolar disorder (BD). Mitochondrial functioning plays an important role in regulating synaptic transmission, brain function, and cognition. Neuronal activity is energy dependent and neurons are particularly sensitive to changes in bioenergetic fluctuations, suggesting that mitochondria regulate fundamental aspects of brain function. Vigorous evidence supports the role of mitochondrial dysfunction in the etiology of BD, including dysregulated oxidative phosphorylation, general decrease of energy, altered brain bioenergetics, co-morbidity with mitochondrial disorders, and association with genetic variants in mitochondrial DNA (mtDNA) or nuclear-encoded mitochondrial genes. Despite these advances, the underlying etiology of mitochondrial dysfunction in BD is unclear. A plausible evolutionary explanation is that mitochondrial-nuclear (mitonuclear) incompatibility leads to a desynchronization of machinery required for efficient electron transport and cellular energy production. Approximately 1,200 genes, encoded from both nuclear and mitochondrial genomes, are essential for mitochondrial function. Studies suggest that mitochondrial and nuclear genomes co-evolve, and the coordinated expression of these interacting gene products are essential for optimal organism function. Incompatibilities between mtDNA and nuclear-encoded mitochondrial genes results in inefficiency in electron flow down the respiratory chain, differential oxidative phosphorylation efficiency, increased release of free radicals, altered intracellular Ca2+ signaling, and reduction of catalytic sites and ATP production. This review explores the role of mitonuclear incompatibility in BD susceptibility and resilience against environmental stressors.
2-Methoxyestradiol Protects Against Lung Ischemia/Reperfusion Injury by Upregulating Annexin A1 Protein Expression
Authors: Liao Wen-I , Wu Shu-Yu , Tsai Shih-Hung , Pao Hsin-Ping , Huang Kun-Lun , Chu Shi-Jye
Published: March 2021

Background: 2-Methoxyestradiol (2ME), a natural 17-β estradiol metabolite, is a potent anti-inflammatory agent, but its effect on ischemia/reperfusion (IR)-induced acute lung inflammation remains unknown. Annexin A1 (AnxA1), a glucocorticoid-regulated protein, is effective at inhibiting neutrophil transendothelial migration by binding the formyl peptide receptors (FPRs). We aimed to investigate whether 2ME upregulates the expression of AnxA1 and protects against IR-induced lung damage.

Methods: IR-mediated acute lung inflammation was induced by ischemia for 40 min followed by reperfusion for 60 min in an isolated, perfused rat lung model. The rat lungs were randomly treated with vehicle or 2ME, and the functional relevance of AnxA1 was determined using an anti-AnxA1 antibody or BOC2 (a pan-receptor antagonist of the FPR). In vitro, human primary alveolar epithelial cells (HPAECs) and rat neutrophils were pretreated with 2ME and an AnxA1 siRNA or anti-AnxA1 antibody and subjected to hypoxia-reoxygenation (HR).

Results: 2ME significantly decreased all lung edema parameters, neutrophil infiltration, oxidative stress, proinflammatory cytokine production, lung cell apoptosis, tight junction protein disruption, and lung tissue injury in the IR-induced acute lung inflammation model. 2ME also increased the expression of the AnxA1 mRNA and protein and suppressed the activation of nuclear factor-κB (NF-κB). In vitro, 2ME attenuated HR-triggered NF-κB activation and interleukin-8 production in HPAECs, decreased transendothelial migration, tumor necrosis factor-α production, and increased apoptosis in neutrophils exposed to HR. These protective effects of 2ME were significantly abrogated by BOC2, the anti-AnxA1 antibody, or AnxA1 siRNA.

Conclusions: 2ME ameliorates IR-induced acute lung inflammation by increasing AnxA1 expression. Based on these results, 2ME may be a promising agent for attenuating IR-induced lung injury.
Strength Exercise Confers Protection in Central Nervous System Autoimmunity by Altering the Gut Microbiota
Authors: Chen Hao , Shen Liping , Liu Yingying , Ma Xiaomeng , Long Ling , Ma Xueying , Ma Lili , Chen Zhaoyu , Lin Xiuli , Si Lei , Chen Xiaohong
Published: March 2021

Exercise therapy including endurance training and resistance training is a promising non-pharmacological therapy in patients with multiple sclerosis (MS). Recent studies have revealed that exercise exerts beneficial impacts on gut microbiota. However, the role of gut microbiota in the immune benefits of strength exercise (SE; one of resistance training) in central nervous system (CNS) autoimmunity is barely known. Here, we observed that 60-min SE ameliorated disease severity and neuropathology in experimental autoimmune encephalomyelitis (EAE), an animal model of MS. SE increased the abundance and diversity of the gut microbiota, and decreased Firmicutes/Bacteroidetes ratio (F/B ratio) and intestinal mucosal permeability, and enrichment of several short-chain fatty acid (SCFA)-producing bacteria. Furthermore, SE reduced Th17 responses and increased Treg responses in the small intestine lymphoid tissues. Compared to the control group, microbiota-depleted mice receiving SE microbiome fecal transplants had lower disease severity and neuropathology scores. These results uncovered a protective role of SE in neuroimmunomodulation effects partly via changes to the gut microbiome.
Antibody Afucosylation Augments CD16-Mediated Serial Killing and IFNγ Secretion by Human Natural Killer Cells
Authors: Karampatzakis Alexandros , Brož Petr , Rey Camille , Önfelt Björn , Cruz De Matos Gabriela Dos Santos , Rycroft Daniel , Ambrose Ashley , Davis Daniel M.
Published: March 2021

One mechanism by which monoclonal antibodies (mAb) help treat cancer or autoimmune disease is through triggering antibody-dependent cellular cytotoxicity (ADCC)viaCD16 on Natural Killer (NK) cells. Afucosylation is known to increase the affinity of mAbs for CD16 on NK cells and here, we set out to assess how mAb afucosylation affects the dynamics of NK cell interactions, receptor expression and effector functions. An IgG1 version of a clinically important anti-CD20 mAb was compared to its afucosylated counterpart (anti-CD20-AF). Opsonization of CD20-expressing target cells, 721.221 or Daudi, with anti-CD20-AF increased NK cell cytotoxicity and IFNγ secretion, compared to anti-CD20. The afucosylated mAb also caused a more rapid and greater loss of CD16 from NK cell surfaces. Loss of CD16 has recently been shown to be important for NK cell detachment and sequential engagement of multiple target cells. Here, live-cell time-lapse microscopy of individual cell-cell interactions in an aqueous environment and a three-dimensional matrix, revealed that anti-CD20-AF induced more rapid killing of opsonized target cells. In addition, NK cells detached more quickly from target cells opsonized with anti-CD20-AF compared to anti-CD20, which increased engagement of multiple targets and enabled a greater proportion of NK cells to perform serial killing. Inhibition of CD16 shedding with TAPI-0 led to reduced detachment and serial killing. Thus, disassembly of the immune synapse caused by loss of cell surface CD16 is a factor determining the efficiency of ADCC and antibody afucosylation alters the dynamics of intercellular interactions to boost serial killing.
Case Report: Omalizumab for Chronic Spontaneous Urticaria in Pregnancy
Authors: Liao Shuang-Lu , Yu Miao , Zhao Zuo-Tao , Maurer Marcus
Published: March 2021

Most chronic spontaneous urticaria (CSU) patients are female, and pregnancy can aggravate the disease activity of patients, but little is known about the efficacy and safety of omalizumab in pregnant CSU patients. We report two pregnant CSU patients treated with omalizumab and review the published information on omalizumab treatment during 11 pregnancies. The outcomes reported on patients with known pregnancies showed they had normal pregnancies and healthy babies as well as complete control of their CSU. The two new cases we reported support the view that omalizumab could be an effective and safe treatment option for pregnant and breastfeeding CSU patients. Further high-quality studies need to be carried out in order to obtain more information on the long-term efficacy and safety of the use of omalizumab during pregnancy in patients with chronic urticaria, including CSU.
Genomic Insights Into Last-Line Antimicrobial Resistance in Multidrug-Resistant Staphylococcus and Vancomycin-Resistant Enterococcus
Authors: Turner Adrianna M. , Lee Jean Y. H. , Gorrie Claire L. , Howden Benjamin P. , Carter Glen P.
Published: March 2021

Multidrug-resistant Staphylococcus and vancomycin-resistant Enterococcus (VRE) are important human pathogens that are resistant to most clinical antibiotics. Treatment options are limited and often require the use of ‘last-line’ antimicrobials such as linezolid, daptomycin, and in the case of Staphylococcus, also vancomycin. The emergence of resistance to these last-line antimicrobial agents is therefore of considerable clinical concern. This mini-review provides an overview of resistance to last-line antimicrobial agents in Staphylococcus and VRE, with a particular focus on how genomics has provided critical insights into the emergence of resistant clones, the molecular mechanisms of resistance, and the importance of mobile genetic elements in the global spread of resistance to linezolid.
On the SARS-CoV-2 “Variolation Hypothesis”: No Association Between Viral Load of Index Cases and COVID-19 Severity of Secondary Cases
Authors: Trunfio Mattia , Longo Bianca Maria , Alladio Francesca , Venuti Francesco , Cerutti Francesco , Ghisetti Valeria , Bonora Stefano , Di Perri Giovanni , Calcagno Andrea
Published: March 2021

Background: Emerging evidence supports the “variolation hypothesis” in severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), but the derivative idea that the viral load of index cases may predict disease severity in secondary cases could be unsubstantiated. We assessed whether the prevalence of symptomatic infections, hospitalization, and deaths in household contacts of 2019 novel coronavirus disease (COVID-19) cases differed according to the SARS-CoV-2 PCR cycle threshold (Ct) from nasal-pharyngeal swab at diagnosis of linked index cases.

Methods: Cross-sectional study on household contacts of COVID-19 cases randomly sampled from all the infections diagnosed in March at our Microbiology Laboratory (Amedeo di Savoia, Turin). Data were retrospectively collected by phone interviews and from the Piedmont regional platform for COVID-19 emergency. Index cases were classified as high (HVl) and low viral load (LVl) according to two exploratory cut-offs of RdRp gene Ct value. Secondary cases were defined as swab confirmed or symptom based likely when not tested but presenting compatible clinical picture.

Results: One hundred thirty-two index cases of whom 87.9% symptomatic and 289 household contacts were included. The latter were male and Caucasian in 44.3 and 95.8% of cases, with a median age of 34 years (19–57). Seventy-four were swab confirmed and other 28 were symptom based likely secondary cases. Considering both, the contacts of HVl and LVl did not differ in the prevalence of symptomatic infections nor COVID-19-related hospitalization and death. No difference in median Ct of index cases between symptomatic and asymptomatic, hospitalized and not hospitalized, or deceased and survived secondary cases was found. Negative findings were confirmed after adjusting for differences in time between COVID-19 onset and swab collection of index cases (median 5 days) and after removing pediatric secondary cases.

Conclusions: The amount of SARS-CoV-2 of the source at diagnosis does not predict clinical outcomes of linked secondary cases. Considering the impelling release of assays for SARS-CoV-2 RNA exact quantification, these negative findings should inform clinical and public health strategies on how to interpret and use the data.
Fungal Diversity and Community Assembly of Ectomycorrhizal Fungi Associated With Five Pine Species in Inner Mongolia, China
Authors: Wang Yong-Long , Zhang Xuan , Xu Ying , Babalola Busayo Joshua , Xiang Si-Min , Zhao Yan-Ling , Fan Yong-Jun
Published: March 2021

Ectomycorrhizal (EM) fungi play vital roles in ensuring host plants’ health, plant diversity, and the functionality of the ecosystem. However, EM fungal diversity, community composition, and underlying assembly processes in Inner Mongolia, China, where forests are typically semiarid and cold-temperate zones, attract less attention. In this study, we investigated EM fungal communities from 63 root samples of five common pine plants in Inner Mongolia across 1,900 km using Illumina Miseq sequencing of the fungal internal transcribed spacer 2 region. We evaluated the impact of host plant phylogeny, soil, climatic, and spatial variables on EM fungal diversity and community turnover. Deterministic vs. stochastic processes for EM fungal community assembly were quantified using β-nearest taxon index scores. In total, we identified 288 EM fungal operational taxonomic units (OTUs) belonging to 31 lineages, of which the most abundant lineages were Tomentella–Thelephora, Wilcoxina, Tricholoma, and Suillus–Rhizopogon. Variations in EM fungal OTU richness and community composition were significantly predicted by host phylogeny, soil (total nitrogen, phosphorus, nitrogen–phosphorus ratio, and magnesium), climate, and spatial distance, with the host plant being the most important factor. β-nearest taxon index demonstrated that both deterministic and stochastic processes jointly determined the community assembly of EM fungi, with the predominance of stochastic processes. At the Saihanwula site selected for preference analysis, all plant species (100%) presented significant preferences for EM fungi, 54% of abundant EM fungal OTUs showed significant preferences for host plants, and 26% of pairs of plant species and abundant fungal OTUs exhibited remarkably strong preferences. Overall, we inferred that the high diversity and distinctive community composition of EM fungi associated with natural pine species in Inner Mongolia and the stochastic processes prevailed in determining the community assembly of EM fungi. Our study shed light on the diversity and community assembly of EM fungi associated with common pine species in semiarid and cold temperate forests in Inner Mongolia, China, for the first time and provided a better understanding of the ecological processes underlying the community assembly of mutualistic fungi.
On the Track of the Missing tRNA Genes: A Source of Non-Canonical Functions?
Authors: Ehrlich Ricardo , Davyt Marcos , López Ignacio , Chalar Cora , Marín Mónica
Published: March 2021

Cellular tRNAs appear today as a diverse population of informative macromolecules with conserved general elements ensuring essential common functions and different and distinctive features securing specific interactions and activities. Their differential expression and the variety of post-transcriptional modifications they are subject to, lead to the existence of complex repertoires of tRNA populations adjusted to defined cellular states. Despite the tRNA-coding genes redundancy in prokaryote and eukaryote genomes, it is surprising to note the absence of genes coding specific translational-active isoacceptors throughout the phylogeny. Through the analysis of different releases of tRNA databases, this review aims to provide a general summary about those “missing tRNA genes.” This absence refers to both tRNAs that are not encoded in the genome, as well as others that show critical sequence variations that would prevent their activity as canonical translation adaptor molecules. Notably, while a group of genes are universally missing, others are absent in particular kingdoms. Functional information available allows to hypothesize that the exclusion of isodecoding molecules would be linked to: 1) reduce ambiguities of signals that define the specificity of the interactions in which the tRNAs are involved; 2) ensure the adaptation of the translational apparatus to the cellular state; 3) divert particular tRNA variants from ribosomal protein synthesis to other cellular functions. This leads to consider the “missing tRNA genes” as a source of putative non-canonical tRNA functions and to broaden the concept of adapter molecules in ribosomal-dependent protein synthesis.
Neuroprotective Roles of the Reverse Transsulfuration Pathway in Alzheimer’s Disease
Authors: Paul Bindu Diana
Published: March 2021

The reverse transsulfuration pathway has emerged as a central hub that integrates the metabolism of sulfur-containing amino acids and redox homeostasis. Transsulfuration involves the transfer of sulfur from homocysteine to cysteine. Cysteine serves as the precursor for several sulfur-containing molecules, which play diverse roles in cellular processes. Recent evidence shows that disruption of the flux through the pathway has deleterious consequences. In this review article, I will discuss the actions and regulation of the reverse transsulfuration pathway and its links to other metabolic pathways, which are disrupted in Alzheimer’s disease (AD). The potential nodes of therapeutic intervention are also discussed, which may pave the way for the development of novel treatments.
Spike Generators and Cell Signaling in the Human Auditory Nerve: An Ultrastructural, Super-Resolution, and Gene Hybridization Study
Authors: Liu Wei , Luque Maria , Li Hao , Schrott-Fischer Anneliese , Glueckert Rudolf , Tylstedt Sven , Rajan Gunesh , Ladak Hanif , Agrawal Sumit , Rask-Andersen Helge
Published: March 2021

Background: The human auditory nerve contains 30,000 nerve fibers (NFs) that relay complex speech information to the brain with spectacular acuity. How speech is coded and influenced by various conditions is not known. It is also uncertain whether human nerve signaling involves exclusive proteins and gene manifestations compared with that of other species. Such information is difficult to determine due to the vulnerable, “esoteric,” and encapsulated human ear surrounded by the hardest bone in the body. We collected human inner ear material for nanoscale visualization combining transmission electron microscopy (TEM), super-resolution structured illumination microscopy (SR-SIM), and RNA-scope analysis for the first time. Our aim was to gain information about the molecular instruments in human auditory nerve processing and deviations, and ways to perform electric modeling of prosthetic devices.

Material and Methods: Human tissue was collected during trans-cochlear procedures to remove petro-clival meningioma after ethical permission. Cochlear neurons were processed for electron microscopy, confocal microscopy (CM), SR-SIM, and high-sensitive in situ hybridization for labeling single mRNA transcripts to detect ion channel and transporter proteins associated with nerve signal initiation and conductance.

Results: Transport proteins and RNA transcripts were localized at the subcellular level. Hemi-nodal proteins were identified beneath the inner hair cells (IHCs). Voltage-gated ion channels (VGICs) were expressed in the spiral ganglion (SG) and axonal initial segments (AISs). Nodes of Ranvier (NR) expressed Nav1.6 proteins, and encoding genes critical for inter-cellular coupling were disclosed.

Discussion: Our results suggest that initial spike generators are located beneath the IHCs in humans. The first NRs appear at different places. Additional spike generators and transcellular communication may boost, sharpen, and synchronize afferent signals by cell clusters at different frequency bands. These instruments may be essential for the filtering of complex sounds and may be challenged by various pathological conditions.