bluuebunny/crossref_metadata_2025 huggingface dataset:
Prevented Sudden Cardiac Death and Neurologic Recovery in Inherited Heart Diseases
Authors: Hernández del Rincón Juan P. , Olmo Conesa Mari C. , Rodríguez Serrano Ana , García Pulgar Helena , López Cuenca David , Muñoz Esparza Carmen , Navarro Peñalver Marina , Santos Mateo Juan José , Nicolás Rocamora Elisa , Gil Ortuño Cristina , Sabater-Molina María , Gimeno Blanes Juan Ramón , Pastor Quirante Francisco
Published: March 2021

Introduction: Inherited cardiovascular diseases are an important cause of sudden cardiac death (SD). The use of risk scores identify high risk patients who would benefit from an implantable cardioverter-defibrillators (ICDs). The development of automated devices for out-of-hospital cardiac arrest improves early resuscitation. The objective of the study is to quantify prevented SD and the neurological recovery of patients with inherited cardiovascular diseases.

Methods: Two hundred fifty-seven cases of SD (age 42 ± 18 years, 79.4% men) of non-ischemic cardiac cause were prospectively collected during the study period (2009–17). Fifty three (20.6%) had a resuscitated cardiac arrest (RCA) (age 40 ± 18 years, 64.2% male). Epidemiological, clinical and autopsy aspects were analyzed. Prevented SD was defined as a combination of RCA and appropriate ICD therapy cases.

Results: An autopsy was performed in 157/204 (77.0%) cases who died. There were 19 (12.1%) cases with a negative autopsy. The diagnosis of cardiomyopathy and channelopathy was 58.0 and 18.7%, respectively. Female sex and confirmed or suspected channelopathy were associated with successful resuscitation. The percentage of prevented SD remained low during the study period (mean 35.6%). 60.4% of RCA cases presented good neurological outcome. There was no association between neurological recovery and therapeutic hypothermia, but there was association with time of resuscitation (min).

Conclusion: A fifth part of non-ischemic cardiac arrests were resuscitated. Female sex and channelopathies were more prevalent among RCA. Two thirds of RCA had a good neurological recovery.
Donepezil Ameliorates Pulmonary Arterial Hypertension by Inhibiting M2-Macrophage Activation
Authors: Qiu Haihua , Zhang Yibo , Li Zhongyu , Jiang Ping , Guo Shuhong , He Yi , Guo Yuan
Published: March 2021

Background: The beneficial effects of parasympathetic stimulation in pulmonary arterial hypertension (PAH) have been reported. However, the specific mechanism has not been completely clarified. Donepezil, an oral cholinesterase inhibitor, enhances parasympathetic activity by inhibiting acetylcholinesterase, whose therapeutic effects in PAH and its mechanism deserve to be investigated.

Methods: The PAH model was established by a single intraperitoneal injection of monocrotaline (MCT, 50 mg/kg) in adult male Sprague-Dawley rats. Donepezil was administered via intraperitoneal injection daily after 1 week of MCT administration. At the end of the study, PAH status was confirmed by echocardiography and hemodynamic measurement. Testing for acetylcholinesterase activity and cholinergic receptor expression was used to evaluate parasympathetic activity. Indicators of pulmonary arterial remodeling and right ventricular (RV) dysfunction were assayed. The proliferative and apoptotic ability of pulmonary arterial smooth muscle cells (PASMCs), inflammatory reaction, macrophage infiltration in the lung, and activation of bone marrow-derived macrophages (BMDMs) were also tested. PASMCs from the MCT-treated rats were co-cultured with the supernatant of BMDMs treated with donepezil, and then, the proliferation and apoptosis of PASMCs were evaluated.

Results: Donepezil treatment effectively enhanced parasympathetic activity. Furthermore, it markedly reduced mean pulmonary arterial pressure and RV systolic pressure in the MCT-treated rats, as well as reversed pulmonary arterial remodeling and RV dysfunction. Donepezil also reduced the proliferation and promoted the apoptosis of PASMCs in the MCT-treated rats. In addition, it suppressed the inflammatory response and macrophage activation in both lung tissue and BMDMs in the model rats. More importantly, donepezil reduced the proliferation and promoted the apoptosis of PASMCs by suppressing M2-macrophage activation.

Conclusion: Donepezil could prevent pulmonary vascular and RV remodeling, thereby reversing PAH progression. Moreover, enhancement of the parasympathetic activity could reduce the proliferation and promote the apoptosis of PASMCs in PAH by suppressing M2-macrophage activation.
Model-Based Assessment of C-Peptide Secretion and Kinetics in Post Gastric Bypass Individuals Experiencing Postprandial Hyperinsulinemic Hypoglycemia
Authors: Schiavon Michele , Herzig David , Hepprich Matthias , Donath Marc Y. , Bally Lia , Dalla Man Chiara
Published: March 2021

Assessment of insulin secretion is key to diagnose postprandial hyperinsulinemic hypoglycemia (PHH), an increasingly recognized complication following bariatric surgery. To this end, the Oral C-peptide Minimal Model (OCMM) can be used. This usually requires fixing C-peptide (CP) kinetics to the ones derived from the Van Cauter population model (VCPM), which has never been validated in PHH individuals. The objective of this work was to test the validity of the OCMM coupled with the VCPM in PHH subjects and propose a method to overcome the observed limitations. Two cohorts of adults with PHH after gastric bypass (GB) underwent either a 75 g oral glucose (9F/3M; age=42±9 y; BMI=28.3±6.9 kg/m2) or a 60 g mixed-meal (7F/3M; age = 43 ± 11 y; BMI=27.5±4.2 kg/m2) tolerance test. The OCMM was identified on CP concentration data with CP kinetics fixed to VCPM (VC approach). In both groups, the VC approach underestimated CP-peak and overestimated CP-tail suggesting CP kinetics predicted by VCPM to be inaccurate in this population. Thus, the OCMM was identified using CP kinetics estimated from the data (DB approach) using a Bayesian Maximum a Posteriori estimator. CP data were well predicted in all the subjects using the DB approach, highlighting a significantly faster CP kinetics in patients with PHH compared to the one predicted by VCPM. Finally, a simulation study was used to validate the proposed approach. The present findings question the applicability of the VCPM in patients with PHH after GB and call for CP bolus experiments to develop a reliable CP kinetic model in this population.
Traumatic Brain Injury as Frequent Cause of Hypopituitarism and Growth Hormone Deficiency: Epidemiology, Diagnosis, and Treatment
Authors: Gasco Valentina , Cambria Valeria , Bioletto Fabio , Ghigo Ezio , Grottoli Silvia
Published: March 2021

Traumatic brain injury (TBI)-related hypopituitarism has been recognized as a clinical entity for more than a century, with the first case being reported in 1918. However, during the 20th century hypopituitarism was considered only a rare sequela of TBI. Since 2000 several studies strongly suggest that TBI-mediated pituitary hormones deficiency may be more frequent than previously thought. Growth hormone deficiency (GHD) is the most common abnormality, followed by hypogonadism, hypothyroidism, hypocortisolism, and diabetes insipidus. The pathophysiological mechanisms underlying pituitary damage in TBI patients include a primary injury that may lead to the direct trauma of the hypothalamus or pituitary gland; on the other hand, secondary injuries are mainly related to an interplay of a complex and ongoing cascade of specific molecular/biochemical events. The available data describe the importance of GHD after TBI and its influence in promoting neurocognitive and behavioral deficits. The poor outcomes that are seen with long standing GHD in post TBI patients could be improved by GH treatment, but to date literature data on the possible beneficial effects of GH replacement therapy in post-TBI GHD patients are currently scarce and fragmented. More studies are needed to further characterize this clinical syndrome with the purpose of establishing appropriate standards of care. The purpose of this review is to summarize the current state of knowledge about post-traumatic GH deficiency.
Epithelial–Mesenchymal Transition in the Resistance to Somatostatin Receptor Ligands in Acromegaly
Authors: Gil Joan , Jordà Mireia , Soldevila Berta , Puig-Domingo Manel
Published: March 2021

Epithelial-mesenchymal transition (EMT) is a dynamic process by which epithelial cells loss their phenotype and acquire mesenchymal traits, including increased migratory and invasive capacities. EMT is involved in physiological processes, such as embryogenesis and wound healing, and in pathological processes such as cancer, playing a pivotal role in tumor progression and metastasis. Pituitary tumors, although typically benign, can be locally invasive. Different studies have shown the association of EMT with increased tumor size and invasion in pituitary tumors, and in particular with a poor response to Somatostatin Receptor Ligands (SRLs) treatment in GH-producing pituitary tumors, the main cause of acromegaly. This review will summarize the current knowledge regarding EMT and SRLs resistance in acromegaly and, based on this relation, will suggest new biomarkers and possible therapies to SRLs resistant tumors.
Associations of Circulating Osteoglycin With Bone Parameters and Metabolic Markers in Patients With Diabetes
Authors: Starup-Linde Jakob Kau , Viggers Rikke , Langdahl Bente , Gregersen Soeren , Lykkeboe Simon , Handberg Aase , Vestergaard Peter
Published: March 2021

Objective

Circulating osteoglycin may facilitate the crosstalk between bone and pancreas to empower adaptation of bone mass to whole body energy balance. We aimed to examine whether osteoglycin is associated with bone and metabolic parameters and if osteoglycin levels differ between patients with type 1 and 2 diabetes (T1D and T2D).

Design and methods

A cross-sectional study of 190 patients with diabetes mellitus and stable hemoglobin A1c (HbA1c) (97 T1D and 93 T2D) was conducted. S-osteoglycin was analyzed by ELISA. Unpaired t-tests were performed to test differences between patients with T1D and T2D and linear regression analyses were performed to investigate associations between osteoglycin, glycemic markers, bone turnover markers and characteristics.

Results

S-osteoglycin did not differ between patients with T1D and T2D (p=0.10). No associations were present between osteoglycin and age, gender, microvascular complications, HbA1c, or plasma glucose in T1D or T2D patients (p>0.05 for all). S-osteoglycin was not associated with levels of bone turnover markers (C-terminal cross-linked telopeptide of type-I collagen (CTX), P-procollagen type 1 amino terminal propeptide (P1NP), P-osteocalcin (OC), P-sclerostin, S-osteoprotegerin (OPG) or S-Receptor Activator of Nuclear factor Kappa beta Ligand (RANKL)) in neither T1D or T2D patients (p>0.05 for all).

Conclusion

Osteoglycin levels were similar in T1D and T2D patients. Osteoglycin did not correlate with glucose, HbA1c or any other biochemical marker of bone turnover. Thus, we did not find evidence supporting the existence of an osteoglycin-bone-pancreas axis.

Clinical Trial Registration

ClinicalTrials.gov, identifier NCT01870557.
Exploring the Use of Environmental DNA (eDNA) to Detect Animal Taxa in the Mesopelagic Zone
Authors: Govindarajan Annette F. , Francolini Rene D. , Jech J. Michael , Lavery Andone C. , Llopiz Joel K. , Wiebe Peter H. , Zhang Weifeng (Gordon)
Published: March 2021

Animal biodiversity in the ocean’s vast mesopelagic zone is relatively poorly studied due to technological and logistical challenges. Environmental DNA (eDNA) analyses show great promise for efficiently characterizing biodiversity and could provide new insight into the presence of mesopelagic species, including those that are missed by traditional net sampling. Here, we explore the utility of eDNA for identifying animal taxa. We describe the results from an August 2018 cruise in Slope Water off the northeast United States. Samples for eDNA analysis were collected using Niskin bottles during five CTD casts. Sampling depths along each cast were selected based on the presence of biomass as indicated by the shipboard Simrad EK60 echosounder. Metabarcoding of the 18S V9 gene region was used to assess taxonomic diversity. eDNA metabarcoding results were compared with those from net-collected (MOCNESS) plankton samples. We found that the MOCNESS sampling recovered more animal taxa, but the number of taxa detected per liter of water sampled was significantly higher in the eDNA samples. eDNA was especially useful for detecting delicate gelatinous animals which are undersampled by nets. We also detected eDNA changes in community composition with depth, but not with sample collection time (day vs. night). We provide recommendations for applying eDNA-based methods in the mesopelagic including the need for studies enabling interpretation of eDNA signals and improvement of barcode reference databases.
Tempo and Mode: Evidence on a Protracted Split From a Dense Fossil Record
Authors: Kimura Yuri , Flynn Lawrence J. , Jacobs Louis L.
Published: March 2021

Fossil records generally inform paleobiologists about extinct taxa and rates of evolution measured at the scale of millions of years. Good records that are densely sampled through time can reveal species level details such as longevity in local sections. Yet fossil data normally do not address details of lineage microevolution because the density through time of lineage sampling is insufficient to perceive patterns at a precision finer than 106years in most cases. This study concerns details of a splitting event in the evolution of murine rodents, an event for which multiple fossil samples dated to a precision of 105years fortuitously document the tempo and mode of origin of sister species, the stems of two extant tribes of mice. Evolution of early Murinae in the northern part of the biogeographically restricted Indian subcontinent between 11.6 and 10.5 Ma involved cladogenesis of two crown taxa, the extant tribes Murini and Arvicanthini. Large samples of fossil rodent teeth document their divergence from a common morphological pool. Definitive basal Murini and Arvicanthini at 10.5 Ma are similar in size and differ by subtle features of the dentition. Those features occur sporadically in the common pool of older fossil teeth at 11.2, 11.4, and 11.6 Ma as inconsistent polymorphisms. Interpreted as a single lineage in the 11.6–11.2 Ma interval, variability of this abundant murine incorporated the roots of the two crown tribes. The pattern through time suggests morphological stasis for several hundred thousand years prior to splitting. This special case informs us on one example of evolution and shows that the tempo of splitting evolution in some cases may be measured in hundreds of thousands of years, followed by stasis once daughter species have differentiated morphologically.
Function Analysis of MBF1, a Factor Involved in the Response to Amino Acid Starvation and Virulence in Candida albicans
Authors: Amorim-Vaz Sara , Coste Alix T. , Tran Van Du T. , Pagni Marco , Sanglard Dominique
Published: March 2021

Candida albicans is a commensal of human mucosae, but also one of the most common fungal pathogens of humans. Systemic infections caused by this fungus, mostly affecting immunocompromised patients, are associated to fatality rates as high as 50% despite the available treatments. In order to improve this situation, it is necessary to fully understand how C. albicans is able to cause disease and how it copes with the host defenses. Our previous studies have revealed the importance of the C. albicans gene MBF1 in virulence and ability to colonize internal organs of mammalian and insect hosts. MBF1 encodes a putative transcriptional regulator, and as such it likely has an impact in the regulation of C. albicans gene expression during host infection. Here, recent advances in RNA-seq technologies were used to obtain a detailed analysis of the impact of MBF1 on C. albicans gene expression both in vitro and during infection. MBF1 was involved in the regulation of several genes with a role in glycolysis and response to stress, particularly to nutritional stress. We also investigated whether an interaction existed between MBF1 and GCN4, a master regulator of response to starvation, and found that both genes were needed for resistance to amino acid starvation, suggesting some level of interaction between the two. Reinforcing this idea, we showed that the proteins encoded by both genes could interact. Consistent with the role of MBF1 in virulence, we also established that GCN4 was necessary for virulence in the mouse model of systemic infection as well as in the Galleria mellonella infection model.
Genome Editing in iPSC-Based Neural Systems: From Disease Models to Future Therapeutic Strategies
Authors: McTague Amy , Rossignoli Giada , Ferrini Arianna , Barral Serena , Kurian Manju A.
Published: March 2021

Therapeutic advances for neurological disorders are challenging due to limited accessibility of the human central nervous system and incomplete understanding of disease mechanisms. Many neurological diseases lack precision treatments, leading to significant disease burden and poor outcome for affected patients. Induced pluripotent stem cell (iPSC) technology provides human neuronal cells that facilitate disease modeling and development of therapies. The use of genome editing, in particular CRISPR-Cas9 technology, has extended the potential of iPSCs, generating new models for a number of disorders, including Alzheimers and Parkinson Disease. Editing of iPSCs, in particular with CRISPR-Cas9, allows generation of isogenic pairs, which differ only in the disease-causing mutation and share the same genetic background, for assessment of phenotypic differences and downstream effects. Moreover, genome-wide CRISPR screens allow high-throughput interrogation for genetic modifiers in neuronal phenotypes, leading to discovery of novel pathways, and identification of new therapeutic targets. CRISPR-Cas9 has now evolved beyond altering gene expression. Indeed, fusion of a defective Cas9 (dCas9) nuclease with transcriptional repressors or activation domains allows down-regulation or activation of gene expression (CRISPR interference, CRISPRi; CRISPR activation, CRISPRa). These new tools will improve disease modeling and facilitate CRISPR and cell-based therapies, as seen for epilepsy and Duchenne muscular dystrophy. Genome engineering holds huge promise for the future understanding and treatment of neurological disorders, but there are numerous barriers to overcome. The synergy of iPSC-based model systems and gene editing will play a vital role in the route to precision medicine and the clinical translation of genome editing-based therapies.
Homozygous of MRP4 Gene rs1751034 C Allele Is Related to Increased Risk of Intravenous Immunoglobulin Resistance in Kawasaki Disease
Authors: Wang Yanfei , Xu Yufen , Huang Ping , Che Di , Wang Zhouping , Huang Xijing , Xie Xiaofei , Li Wei , Zhang Li , Gu Xiaoqiong
Published: March 2021

Background: Kawasaki disease (KD) is a systemic vasculitis in childhood, which mainly causes damage to coronary arteries, and intravenous immunoglobulin (IVIG) is the initial therapy. IVIG resistance increased risk of coronary complication in KD. And genetic background is involved in the occurrence of IVIG resistance. Our previous study indicated the susceptibility of Multi-drug resistance protein 4 (MRP4) SNPs to KD. This study was to clarify the relationship between MRP4 polymorphisms and IVIG resistance.

Methods: We genotyped the six polymorphisms of MRP4 gene in 760 cases of KD using Taqman methods.

Results: Among the six polymorphisms, only the rs1751034 polymorphism was significantly associated with IVIG resistance in KD [CC vs. TT: adjusted odds ratio (OR) = 2.54, 95% confidence interval (CI) = 1.21–5.34; CC vs. TT/TC: adjusted OR = 2.33, 95% CI = 1.12–4.83, p = 0.023]. Combined analysis of three polymorphisms indicated that patients with 3–6 risk genotypes exhibited significantly elevated risk of IVIG resistance, when compared with those with 0–2 risk genotypes (adjusted OR = 1.52, 95% CI = 1.04–2.22, p = 0.0295). Stratified analysis revealed that in term of age and gender, rs1751034 CC carriers were associated with increased risk of IVIG resistance in those aged ≤ 60 months (adjusted OR = 2.65, 95% CI = 1.23–5.71, p = 0.0133). The presence of three or more risk genotypes was significantly associated with risk of IVIG resistance in children younger than 5 years of age and males.

Conclusion: Our results suggest that MRP4 rs1751034 CC is associated with increased risk of IVIG resistance in KD.
Investigations of Kidney Dysfunction-Related Gene Variants in Sickle Cell Disease Patients in Cameroon (Sub-Saharan Africa)
Authors: Ngo-Bitoungui Valentina J. , Belinga Suzanne , Mnika Khuthala , Masekoameng Tshepiso , Nembaware Victoria , Essomba René G. , Ngo-Sack Francoise , Awandare Gordon , Mazandu Gaston K. , Wonkam Ambroise
Published: March 2021

Background

Renal dysfunctions are associated with increased morbidity and mortality in sickle cell disease (SCD). Early detection and subsequent management of SCD patients at risk for renal failure and dysfunctions are essential, however, predictors that can identify patients at risk of developing renal dysfunction are not fully understood.

Methods

In this study, we have investigated the association of 31 known kidney dysfunctions-related variants detected in African Americans from multi-ethnic genome wide studies (GWAS) meta-analysis, to kidney-dysfunctions in a group of 413 Cameroonian patients with SCD. Systems level bioinformatics analyses were performed, employing protein-protein interaction networks to further interrogate the putative associations.

Results

Up to 61% of these patients had micro-albuminuria, 2.4% proteinuria, 71% glomerular hyperfiltration, and 5.9% had renal failure. Six variants are significantly associated with the two quantifiable phenotypes of kidney dysfunction (eGFR and crude-albuminuria): A1CF-rs10994860 (P = 0.02020), SYPL2-rs12136063 (P = 0.04208), and APOL1 (G1)-rs73885319 (P = 0.04610) are associated with eGFR; and WNT7A-rs6795744 (P = 0.03730), TMEM60-rs6465825 (P = 0.02340), and APOL1 (G2)-rs71785313 (P = 0.03803) observed to be protective against micro-albuminuria. We identified a protein-protein interaction sub-network containing three of these gene variants: APOL1, SYPL2, and WNT7A, connected to the Nuclear factor NF-kappa-B p105 subunit (NFKB1), revealed to be essential and might indirectly influence extreme phenotypes. Interestingly, clinical variables, including body mass index (BMI), systolic blood pressure, vaso-occlusive crisis (VOC), and haemoglobin (Hb), explain better the kidney phenotypic variations in this SCD population.

Conclusion

This study highlights a strong contribution of haematological indices (Hb level), anthropometric variables (BMI, blood pressure), and clinical events (i.e., vaso-occlusive crisis) to kidney dysfunctions in SCD, rather than known genetic factors. Only 6/31 characterised gene-variants are associated with kidney dysfunction phenotypes in SCD samples from Cameroon. The data reveal and emphasise the urgent need to extend GWAS studies in populations of African ancestries living in Africa, and particularly for kidney dysfunctions in SCD.
A Critical Role of Peptidylprolyl Isomerase A Pseudogene 22/microRNA-197-3p/Peptidylprolyl Isomerase A Axis in Hepatocellular Carcinoma
Authors: Gu Yuwei , Wang Chao , Chen Shengsen , Tang Jia , Guo Xiaoxiao , Hu Wei , Cui An , Zhang Dian , Yu Kangkang , Chen Mingquan
Published: March 2021

The burden of hepatocellular carcinoma (HCC) worldwide is increasing over time, while the underlying molecular mechanism of HCC development is still under exploration. Pseudogenes are classified as a special type of long non-coding RNAs (lncRNAs), and they played a vital role in regulating tumor-associated gene expression. Here, we report that a pseudogene peptidylprolyl isomerase A pseudogene 22 (PPIAP22) and its parental gene peptidylprolyl isomerase A (PPIA) were upregulated in HCC and were associated with the clinical outcomes of HCC. Further investigation revealed that PPIAP22 might upregulate the expression of PPIA through sponging microRNA (miR)-197-3p, behaving as competing endogenous RNA (ceRNA). PPIA could participate in the development of HCC by regulating mRNA metabolic process and tumor immunity based on the functional enrichment analysis. We also found a strong correlation between the expression levels of PPIA and the immune cell infiltration or the expression of chemokines, especially macrophage, C-C motif chemokine ligand 15 (CCL15), and C-X-C motif chemokine ligand 12 (CXCL12). Our findings demonstrate that the PPIAP22/miR-197-3p/PPIA axis plays a vital role in the progression of HCC by increasing the malignancy of tumor cells and regulating the immune cell infiltration, especially macrophage, through CCL15-CCR1 or CXCL12-CXCR4/CXCR7 pathways.
Specific Host Signatures for the Detection of Tuberculosis Infection in Children in a Low TB Incidence Country
Authors: Dreesman Alexandra , Corbière Véronique , Libin Myriam , Racapé Judith , Collart Philippe , Singh Mahavir , Locht Camille , Mascart Françoise , Dirix Violette
Published: March 2021

Diagnosis of tuberculosis (TB) in children remains challenging due to unspecific clinical presentation and low bacillary load. In low TB incidence countries, most cases are diagnosed by a contact screening strategy after exposure to an index TB case. Due to the severity of TB in young children, the priority is to determine whether a child is infected or not, whereas differential diagnosis between active TB (aTB) and latent TB constitutes a second step. In Belgium, a low TB incidence country, we prospectively included 47 children with a defined M. tuberculosis infection status (12 children with aTB, 18 with latent TB, and 17 uninfected) (exploratory cohort), and determined the optimal combinations of cytokines secreted by their peripheral blood mononuclear cells in response to a 5-days in vitro stimulation with four different mycobacterial antigens, in an attempt to classify the children according to their infectious status. Correct identification of all infected children was obtained by several combinations of two purified protein derivative (PPD)-induced cytokines (IFN-γ and either GM-CSF, MIP-1α, sCD40L or TNF-α), or by combining PPD-induced IFN-γ with culture-filtrate protein-10 (CFP-10)-induced TNF-α. Alternatively, combining CFP-10-induced TNF-α and IP-10 with heparin-binding haemagglutinin (HBHA)-induced-IFN-γ was more effective in testing recently BCG-vaccinated children or those suspected to be infected with non-tuberculous mycobacteria, providing a correct classification of 97% of the M. tuberculosis-infected children. This combination also correctly classified 98% of the children from a validation cohort comprising 40 M. tuberculosis infected children and 20 non-infected children. Further differentiation between aTB and children with latent TB was more difficult. Combining ESAT-6-induced MIP1-α and IP-10, CFP-10-induced MIG, and HBHA-induced MIG provided a correct classification of 77% of the children from the exploratory cohort but only of 57.5% of those from the validation cohort. We conclude that combining the measurement of 2–4 cytokines induced by three different mycobacterial antigens allows an excellent identification of M. tuberculosis-infected children, whereas differentiating children with aTB from those with latent TB remains far from perfect.
Longitudinal Profiling of Antibody Response in Patients With COVID-19 in a Tertiary Care Hospital in Beijing, China
Authors: Feng Xia , Yin Jiming , Zhang Jiaying , Hu Yaling , Ouyang Yabo , Qiao Shubin , Zhao Hong , Zhang Tong , Li Xuemei , Zhang Lili , Zhang Jie , Jin Ronghua , Feng Yingmei , Su Bin
Published: March 2021

The novel coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused a global pandemic of the coronavirus disease 2019 (COVID-19), which elicits a wide variety of symptoms, ranging from mild to severe, with the potential to lead to death. Although used as the standard method to screen patients for SARS-CoV-2 infection, real-time PCR has challenges in dealing with asymptomatic patients and those with an undetectable viral load. Serological tests are therefore considered potent diagnostic tools to complement real-time PCR-based diagnosis and are used for surveillance of seroprevalence in populations. However, the dynamics of the antibody response against SARS-CoV-2 currently remain to be investigated. Here, through analysis of plasma samples from 84 patients with COVID-19, we observed that the response of virus-specific antibodies against three important antigens, RBD, N and S, dynamically changed over time and reached a peak 5–8 weeks after the onset of symptoms. The antibody responses were irrespective of sex. Severe cases were found to have higher levels of antibody response, larger numbers of inflammatory cells and C-reactive protein levels. Within the mild/moderate cases, pairwise comparison indicated moderate association between anti-RBD vs. anti-N, anti-RBD vs. anti-S1S2, and anti-N vs. anti-S1S2. Furthermore, the majority of cases could achieve IgM and IgG seroconversion at 2 weeks since the disease onset. Analysis of neutralizing antibodies indicated that these responses were able to last for more than 112 days but decline significantly after the peak. In summary, our findings demonstrate the longitudinally dynamic changes in antibody responses against SARS-CoV-2, which can contribute to the knowledge of humoral immune response after SARS-CoV-2 infection and are informative for future development of vaccine and antibody-based therapies.
Harnessing Mesenchymal Stromal Cells for the Engineering of Human Hematopoietic Niches
Authors: Pievani Alice , Savoldelli Roberto , Poelchen Juliane , Mattioli Elisa , Anselmi Giorgio , Girardot Alice , Utikal Jochen , Bourdely Pierre , Serafini Marta , Guermonprez Pierre
Published: March 2021

Tissue engineering opens multiple opportunities in regenerative medicine, drug testing, and modeling of the hematopoiesis in health and disease. Recapitulating the organization of physiological microenvironments supporting leukocyte development is essential to model faithfully the development of immune cells. Hematopoietic organs are shaped by spatially organized niches defined by multiple cellular contributions. A shared feature of immune niches is the presence of mesenchymal stromal cells endowed with unique roles in organizing niche development, maintenance, and function. Here, we review challenges and opportunities in harnessing stromal cells for the engineering of artificial immune niches and hematopoietic organoids recapitulating leukocyte ontogeny both in vitro and in vivo.
Group 3 Innate Lymphoid Cells Protect Steatohepatitis From High-Fat Diet Induced Toxicity
Authors: Hamaguchi Masahide , Okamura Takuro , Fukuda Takuya , Nishida Kensuke , Yoshimura Yuta , Hashimoto Yoshitaka , Ushigome Emi , Nakanishi Naoko , Majima Saori , Asano Mai , Yamazaki Masahiro , Takakuwa Hiroshi , Kita Masakazu , Fukui Michiaki
Published: March 2021

Background and Aims: Emerging evidence has revealed that innate lymphoid cells (ILCs) play a key role in regulating metabolic disorders. Here, we investigated the role of group 3 ILCs (ILC3s) in the modulation of Non-alcoholic fatty liver disease (NAFLD).

Methods: RORγ gfp/gfp (RORgt KI/KI) and Rag2−/− mice with the administration of A213, RORgt antagonist, fed with a high-fat-diet (HFD) for 12 weeks, were used. We performed flow cytometry, real time PCR, and lipidomics analysis of serum and liver, and used RAW264.7 cells and murine primary hepatocytes in vitro.

Results: HFD increased ILC3s and M1 macrophages in the liver, and RORgt KI/KI mice deficient in ILC3 showed significant fatty liver, liver fibrosis and significantly increased palmitic acid levels in serum and liver. In addition, administration of A213 to Rag2−/− mice caused significant fatty liver, liver fibrosis, and a significant increase in serum and liver palmitate concentrations, as in RORgt KI/KI mice. Addition of palmitc acid stimulated IL-23 production in cell experiments using RAW264.7. IL-22 produced by ILC3s inhibited the palmitate-induced apoptosis of primary hepatocytes.

Conclusions: HFD stimulates IL-23 production by M1 macrophages, thus promoting ILC3 proliferation, whereas IL-22 secreted by ILC3s contributes to the upregulation of hepatic lipid metabolism and has anti-apoptosis activity.
Beyond First-Line Immune Checkpoint Inhibitor Therapy in Patients With Hepatocellular Carcinoma
Authors: Sharma Rohini , Motedayen Aval Leila
Published: March 2021

Until recently, the treatment landscape for hepatocellular cancer (HCC) was dominated by tyrosine kinase inhibitors (TKIs) which offered an overall survival (OS) benefit when used both in the first-and second-line setting compared to best supportive care. However, the treatment landscape has changed with the introduction of immune checkpoint inhibitors (ICIs) for the treatment of HCC with significant improvement in OS and progression free survival reported with combination atezolizumab and bevacizumab compared to sorafenib in the first-line setting. Nonetheless, the response to ICIs is 20–30% and invariably patients will progress. What remains unclear is which therapeutics should be used following ICI exposure. Extrapolating from the evidence base in renal cell carcinoma, subsequent therapy with TKIs offers both a response and survival benefit and are recommended by European guidelines. However, there are a number of novel therapies emerging that target mechanisms of ICI resistance that hold promise both in combination with ICI or as subsequent therapy. This paper will discuss the evidence for ICIs in HCC, the position of second-line therapies following ICIs and research strategies moving forward.
Methionine and Tryptophan Play Different Modulatory Roles in the European Seabass (Dicentrarchus labrax) Innate Immune Response and Apoptosis Signaling—An In Vitro Study
Authors: Machado Marina , Serra Cláudia R. , Oliva-Teles Aires , Costas Benjamín
Published: March 2021

The range of metabolic pathways that are dependent on a proper supply of specific amino acids (AA) unveils their importance in the support of health. AA play central roles in key pathways vital for immune support and individual AA supplementation has shown to be able to modulate fish immunity. In vitro trials are important tools to evaluate the immunomodulatory role of AA, and the present study was conceived to evaluate methionine and tryptophan roles in immune-related mechanisms aiming to understand their effects in leucocyte functioning and AA pathways. For that purpose, head-kidney leucocytes were isolated and a primary cell culture established. The effect of methionine or tryptophan surplus on cell viability was assessed. Medium L-15 10% FBS without AA addition (0.5mM of L-methionine, 0.1 mM of L-tryptophan) was used as control. To that, L-methionine or L-tryptophan were supplemented at 1 and 2 times (M1x or M2x, and T1x or T2x). Nitric oxide, ATP, total antioxidant capacity, and immune-related genes were evaluated in response to lipopolysaccharides extracted from Photobacterium damselae subsp. piscicida or UV-inactivated bacteria). Moreover, caspase 3 activity and apoptosis-related genes were evaluated in response to the apoptosis-inducing protein, AIP56. Distinct roles in leucocytes’ immune response were observed, with contrasting outcomes in the modulation of individual pathways. Methionine surplus improved cell viability, polyamine production, and methionine-related genes expression in response to an inflammatory agent. Also, methionine supplementation lowered signals of apoptosis by AIP56, presenting lower caspase 3 activity and higher il1β and nf-κb expression. Cells cultured in tryptophan supplemented medium presented signals of an attenuated inflammatory response, with decreased ATP and enhanced expression of anti-inflammatory and catabolism-related genes in macrophages. In response to AIP56, leucocytes cultured in a tryptophan-rich medium presented lower resilience to the toxin, higher caspase 3 activity and expression of caspase 8, and lower expression of several genes, including nf-κb and p65. This study showed the ability of methionine surplus to improve leucocytes’ response to an inflammatory agent and to lower signals of apoptosis by AIP56 induction, while tryptophan attenuated several cellular signals of the inflammatory response to UV-inactivated bacteria and lowered leucocyte resilience to AIP56.
Sensitive Scalp: A Possible Association With the Use of Hair Conditioners
Authors: Brenaut Emilie , Misery Laurent , Legeas Cécile , Roudot Alain-Claude , Ficheux Anne-Sophie
Published: March 2021

A sensitive scalp is defined by the occurrence of unpleasant sensations (tingling, burning, pain, pruritus) triggered by stimuli that should not cause such sensations. Environmental factors, particularly cosmetics, can be triggering factors. The aims of this study were to assess hair cosmetic product consumption in subjects with sensitive scalp and to perform a clinical evaluation of sensitive scalp. After a dermatological examination, women between the ages of 18 and 65 years with or without a sensitive scalp completed different questionnaires. Their use of hair cosmetics (frequency, amount per application) was recorded. A total of 160 women with a mean age of 41 years were included. Twenty-seven subjects presented with seborrheic dermatitis or psoriasis, so only 133 were included in the analysis. Five percent of the subjects declared they had a very sensitive scalp, 25% had a sensitive scalp, 38% had a slightly sensitive scalp, and 32% had a scalp that was not sensitive. The mean sensitive scalp score (3S) score was 3.7 ± 1.6 in the very sensitive scalp group, 3.6 ± 2.1 in the sensitive group, 1.2 ± 1.2 in the slightly sensitive group and 0.1 ± 0.4 in the non-sensitive group. Two groups were analyzed: the 56 subjects with a sensitive scalp (3S ≥ 2 score) and the 56 subjects with a null 3S score. In the sensitive scalp group, 89% suffered from itch, and 45% suffered from tingling. No parameter (hormonal status, smoking, age, phototype, BMI) was associated with the 3S score. No differences in the exposure to shampoos and masks between the two groups were noted. The exposure to hair conditioners was significantly higher in the sensitive scalp group than in the group without sensitive scalp. Itch is the main symptom of a sensitive scalp. The frequency of a sensitive scalp was lower than that previously described when the subjects with scalp dermatosis were excluded. The amount of hair conditioners used was significantly higher in subjects with sensitive scalp than in those without sensitive scalp, suggesting a possible link.
Current Evidence and Future Perspective of Accuracy of Artificial Intelligence Application for Early Gastric Cancer Diagnosis With Endoscopy: A Systematic and Meta-Analysis
Authors: Jiang Kailin , Jiang Xiaotao , Pan Jinglin , Wen Yi , Huang Yuanchen , Weng Senhui , Lan Shaoyang , Nie Kechao , Zheng Zhihua , Ji Shuling , Liu Peng , Li Peiwu , Liu Fengbin
Published: March 2021

Background & Aims: Gastric cancer is the common malignancies from cancer worldwide. Endoscopy is currently the most effective method to detect early gastric cancer (EGC). However, endoscopy is not infallible and EGC can be missed during endoscopy. Artificial intelligence (AI)-assisted endoscopic diagnosis is a recent hot spot of research. We aimed to quantify the diagnostic value of AI-assisted endoscopy in diagnosing EGC.

Method: The PubMed, MEDLINE, Embase and the Cochrane Library Databases were searched for articles on AI-assisted endoscopy application in EGC diagnosis. The pooled sensitivity, specificity, and area under the curve (AUC) were calculated, and the endoscopists' diagnostic value was evaluated for comparison. The subgroup was set according to endoscopy modality, and number of training images. A funnel plot was delineated to estimate the publication bias.

Result: 16 studies were included in this study. We indicated that the application of AI in endoscopic detection of EGC achieved an AUC of 0.96 (95% CI, 0.94–0.97), a sensitivity of 86% (95% CI, 77–92%), and a specificity of 93% (95% CI, 89–96%). In AI-assisted EGC depth diagnosis, the AUC was 0.82(95% CI, 0.78–0.85), and the pooled sensitivity and specificity was 0.72(95% CI, 0.58–0.82) and 0.79(95% CI, 0.56–0.92). The funnel plot showed no publication bias.

Conclusion: The AI applications for EGC diagnosis seemed to be more accurate than the endoscopists. AI assisted EGC diagnosis was more accurate than experts. More prospective studies are needed to make AI-aided EGC diagnosis universal in clinical practice.
Genetic Basis of Antimicrobial Resistant Gram-Negative Bacteria Isolated From Bloodstream in Brazil
Authors: Silveira Melise Chaves , Rocha-de-Souza Cláudio Marcos , de Oliveira Santos Ivson Cassiano , Pontes Leilane da Silva , Oliveira Thamirys Rachel Tavares e , Tavares-Teixeira Camila Bastos , Cossatis Nataly de Almeida , Pereira Natacha Ferreira , da Conceição-Neto Orlando Carlos , da Costa Bianca Santos , Rodrigues Daiana Cristina Silva , Albano Rodolpho Mattos , da Silva Fabrício Alves Barbosa , Marques Elizabeth Andrade , Leão Robson Souza , Carvalho-Assef Ana Paula D'Alincourt
Published: March 2021

Multidrug-resistant microorganisms are a well-known global problem, and gram-negative bacilli are top-ranking. When these pathogens are associated with bloodstream infections (BSI), outcomes become even worse. Here we applied whole-genome sequencing to access information about clonal distribution, resistance mechanism diversity and other molecular aspects of gram-negative bacilli (GNB) isolated from bloodstream infections in Brazil. It was possible to highlight international high-risk clones circulating in the Brazilian territory, such as CC258 for Klebsiella pneumoniae, ST79 for Acinetobacter baumannii and ST233 for Pseudomonas aeruginosa. Important associations can be made such as a negative correlation between CRISPR-Cas and K. pneumoniae CC258, while the genes blaTEM, blaKPC and blaCTX−M are highly associated with this clone. Specific relationships between A. baumannii clones and blaOXA−51 variants were also observed. All P. aeruginosa ST233 isolates showed the genes blaVIM and blaOXA486. In addition, some trends could be identified, where a new P. aeruginosa MDR clone (ST3079), a novel A. baumannii clonal profile circulating in Brazil (ST848), and important resistance associations in the form of blaVIM−2 and blaIMP−56 being found together in one ST233 strain, stand out. Such findings may help to develop approaches to deal with BSI and even other nosocomial infections caused by these important GNB.
Tenofovir Disoproxil Fumarate Is Superior to Entecavir in Reducing Hepatitis B Surface Antigen for Chronic Hepatitis B in China: 2-Year Comprehensive Comparative Result of a Matched Comparative Study
Authors: Yang Sisi , Ma Xueqing , Cai Chengwei , Wang Huanqiu , Xiao Fenqiang , Yu Chengbo
Published: March 2021

Aim: Tenofovir disoproxil fumarate (TDF) and entecavir (ETV) are equally recommended as the first-line antiviral treatments for chronic hepatitis B (CHB) at present. We aimed to compare the long-term efficacy and safety between ETV and TDF therapy in CHB patients who had not received nucleoside analog treatment.

Method: In this single-center retrospective study, 414 patients who received ETV (290 patients) or TDF (124 patients) therapy at our center from January 2017 to May 2019 were included. To reduce the imbalance of baseline variables, propensity score matching (PSM) was employed to yield 124 pairs of patients at a ratio of 1:1 based on the treatment regimen.

Result: After PSM, the cumulative rate of patients who achieved complete virological response (CVR) was not different by drug therapy at each inspection time (1, 3, 6, 12, 18, and 24 months). Subgroup analysis on HBeAg status and level of HBV DNA demonstrated that evolution of proportion of achieving CVR was not significantly different between groups. Despite the insignificant incidence of HBsAg seroclearance in either group, patients in TDF group achieved higher on-treatment HBsAg decline at each inspection time (1, 3, 6, 9, 12, 18, and 24 months), 0.39, 0.51, 0.61, 0.64, 0.68, 0.76, and 0.91 log IU/mL, respectively; while the corresponding reduction were 0.27, 0.37, 0.40, 0.45, 0.48, 0.55, and 0.66 log IU/mL in ETV group (p < 0.05). In subgroup analysis, we found that the significant difference still existed in patients with high baseline HBsAg level (>3 log IU/mL). Additionally, the proportion of patients who achieved on-treatment HBsAg decline >1 log IU/mL in TDF and ETV group was 33.3 and 17.1% (p < 0.01) at the 12th month, 44.4 and 29.5% (p = 0.03) at the 24th month, respectively. Mean increase in serum creatinine from baseline was 0.10 and 0.08 mg/dL in TDF and ETV group (p = 0.11), with no patient experienced acute kidney injury.

Conclusions: TDF has higher potency in reducing HBsAg than ETV in this study. Considering the effect still existed in patients with high HBsAg level (>3 log IU/mL), TDF might be a superior therapeutic regimen combining with its relatively safety.
Targeting Multicopy Prophage Genes for the Increased Detection of Borrelia burgdorferi Sensu Lato (s.l.), the Causative Agents of Lyme Disease, in Blood
Authors: Shan Jinyu , Jia Ying , Teulières Louis , Patel Faizal , Clokie Martha R. J.
Published: March 2021

The successful treatment of Lyme disease (LD) is contingent on accurate diagnosis. However, current laboratory detection assays lack sensitivity in the early stages of the disease. Because delayed diagnosis of LD incurs high healthcare costs and great suffering, new highly sensitive tests are in need. To overcome these challenges, we developed an internally controlled quantitative PCR (Ter-qPCR) that targets the multicopy terminase large subunit (terL) gene encoded by prophages that are only found in LD-causing bacteria. The terL protein helps phages pack their DNA. Strikingly, the detection limit of the Ter-qPCR was analytically estimated to be 22 copies and one bacterial cell in bacteria spiked blood. Furthermore, significant quantitative differences was observed in terms of the amount of terL detected in healthy individuals and patients with either early or late disease. Together, the data suggests that the prophage-targeting PCR has significant power to improve success detection for LD. After rigorous clinical validation, this new test could deliver a step-change in the detection of LD. Prophage encoded markers are prevalent in many other pathogenic bacteria rendering this approach highly applicable to bacterial identification in general.
Improved Yield of Recombinant Protein via Flagella Regulator Deletion in Escherichia coli
Authors: Han Jae-Ho , Jung Sang Taek , Oh Min-Kyu
Published: March 2021

Protein production requires a significant amount of intracellular energy. Eliminating the flagella has been proposed to help Escherichia coli improve protein production by reducing energy consumption. In this study, the gene encoding a subunit of FlhC, a master regulator of flagella assembly, was deleted to reduce the expression of flagella-related genes. FlhC knockout in the ptsG-deleted strain triggered significant growth retardation with increased ATP levels and a higher NADPH/NADP+ ratio. Metabolic flux analysis using a 13C-labeled carbon substrate showed increased fluxes toward the pentose phosphate and tricarboxylic acid cycle pathways in the flhC- and ptsG-deleted strains. Introduction of a high copy number plasmid or overexpression of the recombinant protein in this strain restored growth rate without increasing glucose consumption. These results suggest that the metabolic burden caused by flhC deletion was resolved by recombinant protein production. The recombinant enhanced green fluorescent protein yield per glucose consumption increased 1.81-fold in the flhC mutant strain. Thus, our study demonstrates that high-yield production of the recombinant protein was achieved with reduced flagella formation.