bluuebunny/crossref_metadata_2025 huggingface dataset:
Akt Is S-Palmitoylated: A New Layer of Regulation for Akt
Authors: Blaustein Matías , Piegari Estefanía , Martínez Calejman Camila , Vila Antonella , Amante Analía , Manese María Victoria , Zeida Ari , Abrami Laurence , Veggetti Mariela , Guertin David A. , van der Goot F. Gisou , Corvi María Martha , Colman-Lerner Alejandro
Published: February 2021

The protein kinase Akt/PKB participates in a great variety of processes, including translation, cell proliferation and survival, as well as malignant transformation and viral infection. In the last few years, novel Akt posttranslational modifications have been found. However, how these modification patterns affect Akt subcellular localization, target specificity and, in general, function is not thoroughly understood. Here, we postulate and experimentally demonstrate by acyl-biotin exchange (ABE) assay and 3H-palmitate metabolic labeling that Akt is S-palmitoylated, a modification related to protein sorting throughout subcellular membranes. Mutating cysteine 344 into serine blocked Akt S-palmitoylation and diminished its phosphorylation at two key sites, T308 and T450. Particularly, we show that palmitoylation-deficient Akt increases its recruitment to cytoplasmic structures that colocalize with lysosomes, a process stimulated during autophagy. Finally, we found that cysteine 344 in Akt1 is important for proper its function, since Akt1-C344S was unable to support adipocyte cell differentiation in vitro. These results add an unexpected new layer to the already complex Akt molecular code, improving our understanding of cell decision-making mechanisms such as cell survival, differentiation and death.
CFTR Deficiency Affects Glucose Homeostasis via Regulating GLUT4 Plasma Membrane Transportation
Authors: Gu Junzhong , Zhang Weiwei , Wu Lida , Gu Yuchun
Published: February 2021

Cystic Fibrosis (CF) is an autosomal recessive disorder caused by mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene. CF-related diabetes (CFRD) is one of the most prevalent comorbidities of CF. Altered glucose homeostasis has been reported in CF patients. The mechanism has not been fully elucidated. Besides the consequence of pancreatic endocrine dysfunction, we focus on insulin-responsive tissues and glucose transportation to explain glucose homeostasis alteration in CFRD. Herein, we found that CFTR knockout mice exhibited insulin resistance and glucose tolerance. Furthermore, we demonstrated insulin-induced glucose transporter 4 (GLUT4) translocation to the cell membrane was abnormal in the CFTR knockout mice muscle fibers, suggesting that defective intracellular GLUT4 transportation may be the cause of impaired insulin responses and glucose homeostasis. We further demonstrated that PI(4,5)P2 could rescue CFTR related defective intracellular GLUT4 transportation, and CFTR could regulate PI(4,5)P2 cellular level through PIP5KA, suggesting PI(4,5)P2 is a down-stream signal of CFTR. Our results revealed a new signal mechanism of CFTR in GLUT4 translocation regulation, which helps explain glucose homeostasis alteration in CF patients.
Using a Riboswitch Sensor to Detect Co2+/Ni2+ Transport in E. coli
Authors: Wang Xiaoying , Wei Wei , Zhao Jing
Published: February 2021

Intracellular concentrations of essential mental ions must be tightly maintained to avoid metal deprivation and toxicity. However, their levels in cells are still difficult to monitor. In this report, the combination of a Co2+Ni2+-specific riboswitch and an engineered downstream mCherry fluorescent protein allowed a highly sensitive and selective whole-cell Co2+/Ni2+ detection process. The sensors were applied to examine the resistance system of Co2+/Ni2+in E. coli, and the sensors were able to monitor the effects of genetic deletions. These results indicate that riboswitch-based sensors can be employed in the study of related cellular processes.
Effects of Therapeutic Hypothermia on Normal and Ischemic Heart
Authors: Yamada Kelly P. , Kariya Taro , Aikawa Tadao , Ishikawa Kiyotake
Published: February 2021

Therapeutic hypothermia has been used for treating brain injury after out-of-hospital cardiac arrest. Its potential benefit on minimizing myocardial ischemic injury has been explored, but clinical evidence has yet to confirm positive results in preclinical studies. Importantly, therapeutic hypothermia for myocardial infarction is unique in that it can be initiated prior to reperfusion, in contrast to its application for brain injury in resuscitated cardiac arrest patients. Recent advance in cooling technology allows more rapid cooling of the heart than ever and new clinical trials are designed to examine the efficacy of rapid therapeutic hypothermia for myocardial infarction. In this review, we summarize current knowledge regarding the effect of hypothermia on normal and ischemic hearts and discuss issues to be solved in order to realize its clinical application for treating acute myocardial infarction.
Signs of Deregulated Gene Expression Are Present in Both CD14+ and CD14- PBMC From Non-Obese Men With Family History of T2DM
Authors: Koc Michal , Šiklová Michaela , Šrámková Veronika , Štěpán Marek , Krauzová Eva , Štich Vladimír , Rossmeislová Lenka
Published: February 2021

Aim

Development of type 2 diabetes (T2DM) is associated with disturbances in immune and metabolic status that may be reflected by an altered gene expression profile of peripheral blood mononuclear cells (PBMC). To reveal a potential family predisposition to these alterations, we investigated the regulation of gene expression profiles in circulating CD14+ and CD14- PBMC in fasting conditions and in response to oral glucose tolerance test (OGTT) in glucose tolerant first-degree relatives (FDR) of T2DM patients and in control subjects.

Materials and Methods

This work is based on the clinical study LIMEX (NCT03155412). Non-obese 12 non-diabetic (FDR), and 12 control men without family history of diabetes matched for age and BMI underwent OGTT. Blood samples taken before and at the end of OGTT were used for isolation of circulating CD14+ and CD14- PBMC. In these cells, mRNA levels of 94 genes related to lipid and carbohydrate metabolism, immunity, and inflammation were assessed by qPCR.

Results

Irrespectively of the group, the majority of analyzed genes had different mRNA expression in CD14+ PBMC compared to CD14- PBMC in the basal (fasting) condition. Seven genes (IRS1, TLR2, TNFα in CD14+ PBMC; ABCA1, ACOX1, ATGL, IL6 in CD14- PBMC) had different expression in control vs. FDR groups. OGTT regulated mRNA levels of nine genes selectively in CD14+ PBMC and of two genes (ABCA1, PFKL) selectively in CD14-PBMC. Differences in OGTT-induced response between FDR and controls were observed for EGR2, CCL2 in CD14+ PBMC and for ABCA1, ACOX1, DGAT2, MLCYD, and PTGS2 in CD14- PBMC.

Conclusion

This study revealed a different impact of glucose challenge on gene expression in CD14+ when compared with CD14- PBMC fractions and suggested possible impact of family predisposition to T2DM on basal and OGTT-induced gene expression in these PBMC fractions. Future studies on these putative alterations of inflammation and lipid metabolism in fractionated PBMC in larger groups of subjects are warranted.
Comparative Mitogenomic Analysis Reveals Dynamics of Intron Within and Between Tricholoma Species and Phylogeny of Basidiomycota
Authors: Huang Wenli , Feng Huiyu , Tu Wenying , Xiong Chuan , Jin Xin , Li Ping , Wang Xu , Li Qiang
Published: February 2021

The genus of Tricholoma is a group of important ectomycorrhizal fungi. The overlapping of morphological characteristics often leads to the confusion of Tricholoma species classification. In this study, the mitogenomes of five Tricholoma species were sequenced based on the next-generation sequencing technology, including T. matsutake SCYJ1, T. bakamatsutake, T. terreum, T. flavovirens, and T. saponaceum. These five mitogenomes were all composed of circular DNA molecules, with sizes ranging from 49,480 to 103,090 bp. Intergenic sequences were considered to be the main factor contributing to size variations of Tricholoma mitogenomes. Comparative mitogenomic analysis showed that the introns of the Agaricales mitogenome experienced frequent loss/gain events. In addition, potential gene transfer was detected between the mitochondrial and nuclear genomes of the five species of Tricholoma. Evolutionary analysis showed that the rps3 gene of the Tricholoma species was under positive selection or relaxed selection in the evolutionary process. In addition, large-scale gene rearrangements were detected between some Tricholoma species. Phylogenetic analysis using the Bayesian inference and maximum likelihood methods based on a combined mitochondrial gene set yielded identical and well-supported tree topologies. This study promoted the understanding of the genetics, evolution, and phylogeny of the Tricholoma genus and related species.
IFI16 Can Be Used as a Biomarker for Diagnosis of Renal Cell Carcinoma and Prediction of Patient Survival
Authors: Yu Baozhong , Zheng Xiang , Sun Zejia , Cao Peng , Zhang Jiandong , Wang Wei
Published: February 2021

The incidences of renal cell carcinoma (RCC) increase in number each year and account for about 2–3% of all malignant tumors. Many patients have metastasis by the time of diagnosis, and their prognosis is poor. Therefore, it is essential that new diagnostic and prognostic markers for kidney cancer are identified. In this study, we assessed the potential of IFI16 as a diagnostic and prognostic marker for RCC. We analyzed the TCGA and UALCAN databases and found IFI16 to be highly expressed in ccRCC. In addition, high IFI16 levels positively correlated with lymphatic metastasis, tumor stage, and histopathological grade. Kaplan-Meier curve analysis showed that IFI16 expression was related to the prognosis of patients, and high IFI16 expression indicated a worse overall survival (p = 5.1E–0.7). Receiver operating characteristic curve analysis showed that a combination of IFI16 expression and histopathological grade improved predictive accuracy (AUC = 0.697; 95%CI: 0.628–0.765, P < 0.001). Finally, the relative levels of IFI16 in ACHN and Caki-1 cells were higher than that of HK-2 cells by western blotting analysis and RT-PCR. Functional tests showed that knocking down IFI16 expression inhibited migration and invasion in vitro. Therefore, IFI16 is a potential biomarker for the diagnosis and prognosis of RCC patients.
Gene-Microbiome Co-expression Networks in Colon Cancer
Authors: Uriarte-Navarrete Irving , Hernández-Lemus Enrique , de Anda-Jáuregui Guillermo
Published: February 2021

It is known that cancer onset and development arise from complex, multi-factorial phenomena spanning from the molecular, functional, micro-environmental, and cellular up to the tissular and organismal levels. Important advances have been made in the systematic analysis of the molecular (mostly genomic and transcriptomic) within large studies of high throughput data such as The Cancer Genome Atlas collaboration. However, the role of the microbiome in the induction of biological changes needed to reach these pathological states remains to be explored, largely because of scarce experimental data. In recent work a non-standard bioinformatics strategy was used to indirectly quantify microbial abundance from TCGA RNA-seq data, allowing the evaluation of the microbiome in well-characterized cancer patients, thus opening the way to studies incorporating the molecular and microbiome dimensions altogether. In this work, we used such recently described approaches for the quantification of microbial species alongside with gene expression. With this, we will reconstruct bipartite networks linking microbial abundance and gene expression in the context of colon cancer, by resorting to network reconstruction based on measures from information theory. The rationale is that microbial communities may induce biological changes important for the cancerous state. We analyzed changes in microbiome-gene interactions in the context of early (stages I and II) and late (stages III and IV) colon cancer, studied changes in network descriptors, and identify key discriminating features for early and late stage colon cancer. We found that early stage bipartite network is associated with the establishment of structural features in the tumor cells, whereas late stage is related to more advance signaling and metabolic features. This functional divergence thus arise as a consequence of changes in the organization of the corresponding gene-microorganism co-expression networks.
Why Septic Patients Remain Sick After Hospital Discharge?
Authors: Gritte Raquel Bragante , Souza-Siqueira Talita , Curi Rui , Machado Marcel Cerqueira Cesar , Soriano Francisco Garcia
Published: February 2021

Sepsis is well known to cause a high patient death rate (up to 50%) during the intensive care unit (ICU) stay. In addition, sepsis survival patients also exhibit a very high death rate after hospital discharge compared to patients with any other disease. The addressed question is then: why septic patients remain ill after hospital discharge? The cellular and molecular mechanisms involved in the high rate of septic patient deaths are still unknown. We described herein the studies that investigated the percentage of septic patients that died after hospital discharge ranging from 90 days up to 5 years. We also reported the symptoms of septic patients after hospital discharge and the development of the recently called post-sepsis syndrome (PSS). The most common symptoms of the PSS are cognitive disabilities, physical functioning decline, difficulties in performing routine daily activities, and poor life quality. The PSS also associates with quite often reinfection and re-hospitalization. This condition is the cause of the high rate of death mentioned above. We reported the proportion of patients dying after hospital discharge up to 5 years of followed up and the PSS symptoms associated. The authors also discuss the possible cellular and metabolic reprogramming mechanisms related with the low survival of septic patients and the occurrence of PSS.
The Genetics of Human Schistosomiasis Infection Intensity and Liver Disease: A Review
Authors: Mewamba Estelle M. , Nyangiri Oscar A. , Noyes Harry A. , Egesa Moses , Matovu Enock , Simo Gustave
Published: February 2021

Schistosomiasis remains the fourth most prevalent parasitic disease affecting over 200 million people worldwide. Control efforts have focussed on the disruption of the life cycle targeting the parasite, vector and human host. Parasite burdens are highly skewed, and the majority of eggs are shed into the environment by a minority of the infected population. Most morbidity results from hepatic fibrosis leading to portal hypertension and is not well-correlated with worm burden. Genetics as well as environmental factors may play a role in these skewed distributions and understanding the genetic risk factors for intensity of infection and morbidity may help improve control measures. In this review, we focus on how genetic factors may influence parasite load, hepatic fibrosis and portal hypertension. We found 28 studies on the genetics of human infection and 20 studies on the genetics of pathology in humans.S. mansoniandS. haematobiuminfection intensity have been showed to be controlled by a major quantitative trait locusSM1, on chromosome 5q31-q33 containing several genes involved in the Th2 immune response, and three other loci of smaller effect on chromosomes 1, 6, and 7. The most common pathology associated with schistosomiasis is hepatic and portal vein fibroses and theSM2quantitative trait locus on chromosome six has been linked to intensity of fibrosis. Although there has been an emphasis on Th2 cytokines in candidate gene studies, we found that four of the five QTL regions contain Th17 pathway genes that have been included in schistosomiasis studies:IL17BandIL12BinSM1, IL17AandIL17Fin 6p21-q2,IL6Rin 1p21-q23 andIL22RA2inSM2. The Th17 pathway is known to be involved in response to schistosome infection and hepatic fibrosis but variants in this pathway have not been tested for any effect on the regulation of these phenotypes. These should be priorities for future studies.
DNA Methylation Analysis to Unravel Altered Genetic Pathways Underlying Early Onset and Late Onset Neonatal Sepsis. A Pilot Study
Authors: Lorente-Pozo Sheila , Navarrete Paula , Garzón María José , Lara-Cantón Inmaculada , Beltrán-García Jesús , Osca-Verdegal Rebeca , Mena-Mollá Salvador , García-López Eva , Vento Máximo , Pallardó Federico V. , García-Giménez José Luis
Published: February 2021

Background: Neonatal sepsis is a systemic condition widely affecting preterm infants and characterized by pro-inflammatory and anti-inflammatory responses. However, its pathophysiology is not yet fully understood. Epigenetics regulates the immune system, and its alteration leads to the impaired immune response underlying sepsis. DNA methylation may contribute to sepsis-induced immunosuppression which, if persistent, will cause long-term adverse effects in neonates.

Objective: To analyze the methylome of preterm infants in order to determine whether there are DNA methylation marks that may shed light on the pathophysiology of neonatal sepsis.

Design: Prospective observational cohort study performed in the neonatal intensive care unit (NICU) of a tertiary care center.

Patients: Eligible infants were premature ≤32 weeks admitted to the NICU with clinical suspicion of sepsis. The methylome analysis was performed in DNA from blood using Infinium Human Methylation EPIC microarrays to uncover methylation marks.

Results: Methylation differential analysis revealed an alteration of methylation levels in genomic regions involved in inflammatory pathways which participate in both the innate and the adaptive immune response. Moreover, differences between early and late onset sepsis as compared to normal controls were assessed.

Conclusions: DNA methylation marks can serve as a biomarker for neonatal sepsis and even contribute to differentiating between early and late onset sepsis.
Breaking All the Rules: The First Recorded Hard Substrate Sessile Benthic Community Far Beneath an Antarctic Ice Shelf
Authors: Griffiths Huw J. , Anker Paul , Linse Katrin , Maxwell Jamie , Post Alexandra L. , Stevens Craig , Tulaczyk Slawek , Smith James A.
Published: February 2021

The seafloor beneath floating ice shelves accounts roughly a third of the Antarctic’s 5 million km2 of continental shelf. Prior to this study, our knowledge of these habitats and the life they support was restricted to what has been observed from eight boreholes drilled for geological and glaciological studies. The established theory of sub-ice shelf biogeography is that both functional and taxonomic diversities decrease along a nutrient gradient with distance from the ice shelf front, resulting in a depauperate fauna, dominated by mobile scavengers and predators toward the grounding line. Mobile macro-benthic life and mega-benthic life have been observed as far as 700 km under an ice shelf. New observations from two boreholes in the Filchner-Ronne Ice Shelf challenge the idea that sessile organisms reduce in prevalence the further under the ice you go. The discovery of an established community consisting of only sessile, probably filter feeding, organisms (sponges and other taxa) on a boulder 260 km from the ice front raises significant questions, especially when the local currents suggest that this community is somewhere between 625 km and 1500 km in the direction of water flow from the nearest region of photosynthesis. This new evidence requires us to rethink our ideas with regard to the diversity of community types found under ice shelves, the key factors which control their distribution and their vulnerability to environmental change and ice shelf collapse.
Electrochemical Detection of Environmental Pollutants Based on Graphene Derivatives: A Review
Authors: Kumunda Coster , Adekunle Abolanle S. , Mamba Bhekie B. , Hlongwa Ntuthuko W. , Nkambule Thabo T. I.
Published: February 2021

Population-driven socioeconomic urban expansion, industrialization, and intensified modern agricultural practices are interlinked to environmental challenges culminating in compromised water quality due to pollution by toxic, persistent, and bioaccumulative heavy metal ions, pesticides, nitroaromatics, and other emerging pollutants. Considering the detrimental impact of pollutants on human health and ecosystem, their detection in different media including water is paramount. Notably, electrochemical techniques are more appealing owing to their recognized advantages. This research summarizes and evaluates the most recent advances in the electrochemical sensing of environmental pollutants such as heavy metal ions, pesticides, nitroaromatics, and other distinct emerging contaminants. Besides, the review focuses on the application of electrochemical detection of the selected pollutants through analysis of representative reports in the five years from 2016 to 2020. Therefore, the review is intended to contribute insights and guidelines to contemporary progress in specific electrochemical application practices based on graphene derivatives, toward the aforenamed pollutants. Thus, it focused on sensing methods such as cyclic voltammetry, anodic stripping voltammetry, and electrochemical impedance spectroscopy employing different sensing elements incorporating graphene. Moreover, the review also highlighted graphene synthesis pathways, sensor design strategies, and functionalization. Furthermore, the review showed that there is congruence in the literature that functionalized graphene and its derivatives remain as viable modifiers in electrochemical sensing of pollutants. Nonetheless, the study also appraised the absence of literature reports on electrochemical detection of natural organic matter substances like humic acid and fulvic acid using a graphene-based sensor. In reckoning, current challenges related to graphene synthesis and applicability, envisaged opportunities, and future perspectives are outlined.
The Influence of Charge Motion on Pre-Chamber and Main Chamber Combustion in a Highly Dilute Jet Ignition Engine
Authors: Bunce Michael , Cairns Alasdair , Krishna Pothuraju Subramanyam Sai , Peters Nathan , Blaxill Hugh
Published: February 2021

Though there are multiple viable powertrain options available for the automotive sector, those that contain internal combustion engines will continue to account for the majority of global sales for the next several decades. It is therefore imperative to continue the pursuit of novel combustion concepts that produce efficiency levels significantly higher than those of current engines. Introducing high levels of dilution in spark ignited (SI) engines has consistently proven to produce an efficiency benefit compared to conventional stoichiometric engine operation. However, this combustion mode can present challenges for the ignition system. Pre-chamber jet ignition enables stable, highly dilute combustion by both increasing the ignition energy present in the system and distributing it throughout the combustion chamber. Previous work by the authors have shown that jet ignition produces 15–25% increases in thermal efficiency over baseline SI engines with only relatively minor changes to engine architecture. Lean combustion in general and jet ignition in particular represent fundamentally different engine operating modes compared to those of conventional stoichiometric SI engines. Therefore, there are some system sensitivities not present in stoichiometric engines that must be investigated in order to fully optimize the jet ignition system. Differing types and magnitudes of charge motion are incorporated in SI engines to aid with mixture preparation but the influence of charge motion over lean combustion performance, particularly in jet ignition engines, is less well understood. This study analyzes the impact that charge motion has on both pre-chamber and main chamber combustion. A 1.5 L 3-cylinder gasoline engine is outfitted with multiple intake port configurations producing varying magnitudes and types of charge motion. Pre-chamber and main chamber combustion stability and other burn parameter responses are analyzed across multiple speeds and loads, including at critical operating points such as a catalyst heating condition. The results show that there is combustion sensitivity to charge motion, resulting in >1 percentage point spread in peak thermal efficiency for the configurations tested, and that this sensitivity manifests most significantly under low ignitability conditions such as heavy dilution. These results provide guidance for future system optimization of jet ignition engines.
Silver Nanoparticles Induce a Triclosan-Like Antibacterial Action Mechanism in Multi-Drug Resistant Klebsiella pneumoniae
Authors: Pareek Vikram , Devineau Stéphanie , Sivasankaran Sathesh K. , Bhargava Arpit , Panwar Jitendra , Srikumar Shabarinath , Fanning Séamus
Published: February 2021

Infections associated with antimicrobial-resistant bacteria now represent a significant threat to human health using conventional therapy, necessitating the development of alternate and more effective antibacterial compounds. Silver nanoparticles (Ag NPs) have been proposed as potential antimicrobial agents to combat infections. A complete understanding of their antimicrobial activity is required before these molecules can be used in therapy. Lysozyme coated Ag NPs were synthesized and characterized by TEM-EDS, XRD, UV-vis, FTIR spectroscopy, zeta potential, and oxidative potential assay. Biochemical assays and deep level transcriptional analysis using RNA sequencing were used to decipher how Ag NPs exert their antibacterial action against multi-drug resistant Klebsiella pneumoniae MGH78578. RNAseq data revealed that Ag NPs induced a triclosan-like bactericidal mechanism responsible for the inhibition of the type II fatty acid biosynthesis. Additionally, released Ag+ generated oxidative stress both extra- and intracellularly in K. pneumoniae. The data showed that triclosan-like activity and oxidative stress cumulatively underpinned the antibacterial activity of Ag NPs. This result was confirmed by the analysis of the bactericidal effect of Ag NPs against the isogenic K. pneumoniae MGH78578 ΔsoxS mutant, which exhibits a compromised oxidative stress response compared to the wild type. Silver nanoparticles induce a triclosan-like antibacterial action mechanism in multi-drug resistant K. pneumoniae. This study extends our understanding of anti-Klebsiella mechanisms associated with exposure to Ag NPs. This allowed us to model how bacteria might develop resistance against silver nanoparticles, should the latter be used in therapy.
Genome-Wide Association Studies for the Detection of Genetic Variants Associated With Daptomycin and Ceftaroline Resistance in Staphylococcus aureus
Authors: Weber Robert E. , Fuchs Stephan , Layer Franziska , Sommer Anna , Bender Jennifer K. , Thürmer Andrea , Werner Guido , Strommenger Birgit
Published: February 2021

Background

As next generation sequencing (NGS) technologies have experienced a rapid development over the last decade, the investigation of the bacterial genetic architecture reveals a high potential to dissect causal loci of antibiotic resistance phenotypes. Although genome-wide association studies (GWAS) have been successfully applied for investigating the basis of resistance traits, complex resistance phenotypes have been omitted so far. For S. aureus this especially refers to antibiotics of last resort like daptomycin and ceftaroline. Therefore, we aimed to perform GWAS for the identification of genetic variants associated with DAP and CPT resistance in clinical S. aureus isolates.

Materials/methods

To conduct microbial GWAS, we selected cases and controls according to their clonal background, date of isolation, and geographical origin. Association testing was performed with PLINK and SEER analysis. By using in silico analysis, we also searched for rare genetic variants in candidate loci that have previously been described to be involved in the development of corresponding resistance phenotypes.

Results

GWAS revealed MprF P314L and L826F to be significantly associated with DAP resistance. These mutations were found to be homogenously distributed among clonal lineages suggesting convergent evolution. Additionally, rare and yet undescribed single nucleotide polymorphisms could be identified within mprF and putative candidate genes. Finally, we could show that each DAP resistant isolate exhibited at least one amino acid substitution within the open reading frame of mprF. Due to the presence of strong population stratification, no genetic variants could be associated with CPT resistance. However, the investigation of the staphylococcal cassette chromosome mec (SCCmec) revealed various mecA SNPs to be putatively linked with CPT resistance. Additionally, some CPT resistant isolates revealed no mecA mutations, supporting the hypothesis that further and still unknown resistance determinants are crucial for the development of CPT resistance in S. aureus.

Conclusion

We hereby confirmed the potential of GWAS to identify genetic variants that are associated with antibiotic resistance traits in S. aureus. However, precautions need to be taken to prevent the detection of spurious associations. In addition, the implementation of different approaches is still essential to detect multiple forms of variations and mutations that occur with a low frequency.
Can new immunoassay techniques improve bladder cancer diagnostics With protein biomarkers?
Authors: Shlyapnikov Yuri M. , Malakhova Ekaterina A. , Vinarov Andrey Z. , Zamyatnin Andrey A. , Shlyapnikova Elena A.
Published: February 2021

The search for new diagnostic tests for cancer or ways to improve existing tests is primarily driven by the desire to identify the disease as early as possible. In this report, we summarize the current knowledge of the most promising diagnostic protein bladder cancer (BC) markers reported over the last decade. Unfortunately, analysis of published data suggests that a reliable, highly sensitive biomarker test-system based on ELISA for detecting BC has not yet been developed. The use of more sensitive assays to detect ultra-low concentrations of biomarkers not available for ELISA, could be very beneficial. Based on the literature and pilot experimental data, we conclude that a highly sensitive immunoassay using microarrays and magnetic labels, could be an effective and cheap technique suitable for the detection of diagnostically relevant BC biomarkers.
Integrity of the Prefronto-striato-thalamo-prefrontal Loop Predicts Tai Chi Chuan Training Effects on Cognitive Task-switching in Middle-aged and Older Adults
Authors: Wu Meng-Tien , Tang Pei-Fang , Tseng Wen-Yih Isaac , Hsu Yung-Chin , Chen Yu-Jen , Goh Joshua O. S. , Chou Tai-Li , Chang Yu-Kai , Gau Susan Shur-Fen , Lan Ching
Published: February 2021

Tai Chi Chuan (TCC) exercise has been shown to improve cognitive task-switching performance in older adults, but the extent of this positive effect varies among individuals. Past research also shows that brain white matter integrity could predict behavioral gains of cognitive and motor learning. Therefore, in this randomized controlled trial (NCT02270320), we examined whether baseline integrity of three target white matter tract groups was predictive of task-switching improvement after 12-week TCC training in middle-aged and older adults. Thirty-eight eligible participants were randomly assigned to a TCC group (n = 19) and a control group (n = 19). Cognitive task-switching and physical performances were collected before and after training. Brain diffusion spectrum MR images were acquired before training and the general fractional anisotropy (GFA) of each target white matter tract group was calculated to indicate baseline white matter integrity of that group. Correlation and regression analyses between these GFAs and post-training task-switching improvement were analyzed using adjusted p-values. After 12 weeks, significant task-switching and physical performance improvements were found only in the TCC group. Moreover, higher baseline GFA of the prefronto-striato-thalamo-prefrontal loop fibers (r = −0.63, p = 0.009), but not of the prefronto-parietal/occipital (r = −0.55, p = 0.026) and callosal (r = −0.35, p = 0.189) fiber groups, was associated with greater reductions of task-switching errors after the TCC training. Multiple regression analysis revealed that baseline GFA of the prefronto-striato-thalamo-prefrontal loop fibers was the only independent white matter integrity predictor of task-switching error reductions after TCC training (β = −0.620, adjusted R2 change = 0.265, p = 0.009). These findings not only highlight the important role of baseline integrity of the prefronto-striatal circuits in influencing the extent of positive cognitive task-switching effects from short-term TCC training, but also implicate that preserving good white matter integrity in the aging process may be crucial in order to gain the best cognitive effects of exercise interventions.
Basal Forebrain Atrophy Is Associated With Allocentric Navigation Deficits in Subjective Cognitive Decline
Authors: Chen Qian , Wu Sichu , Li Xin , Sun Yi , Chen Wenqian , Lu Jiaming , Zhang Wen , Liu Jiani , Qing Zhao , Nedelska Zuzana , Hort Jakub , Zhang Xin , Zhang Bing
Published: February 2021

Individuals with subjective cognitive decline (SCD) are at higher risk of incipient Alzheimer's disease (AD). Spatial navigation (SN) impairments in AD dementia and mild cognitive impairment patients have been well-documented; however, studies investigating SN deficits in SCD subjects are still lacking. This study aimed to explore whether basal forebrain (BF) and entorhinal cortex (EC) atrophy contribute to spatial disorientation in the SCD stage. In total, 31 SCD subjects and 24 normal controls were enrolled and administered cognitive scales, a 2-dimensional computerized SN test, and structural magnetic resonance imaging (MRI) scanning. We computed the differences in navigation distance errors and volumes of BF subfields, EC, and hippocampus between the SCD and control groups. The correlations between MRI volumetry and navigation distance errors were also calculated. Compared with the controls, the SCD subjects performed worse in both egocentric and allocentric navigation. The SCD group showed volume reductions in the whole BF (p < 0.05, uncorrected) and the Ch4p subfield (p < 0.05, Bonferroni corrected), but comparable EC and hippocampal volumes with the controls. In the SCD cohort, the allocentric errors were negatively correlated with total BF (r = −0.625, p < 0.001), Ch4p (r = −0.625, p < 0.001), total EC (r = −0.423, p = 0.031), and left EC volumes (r = −0.442, p = 0.024), adjusting for age, gender, years of education, total intracranial volume, and hippocampal volume. This study demonstrates that SN deficits and BF atrophy may be promising indicators for the early detection of incipient AD patients. The reduced BF volume, especially in the Ch4p subfield, may serve as a structural basis for allocentric disorientation in SCD subjects independent of hippocampal atrophy. Our findings may have further implications for the preclinical diagnosis and intervention for potential AD patients.
Working Memory Training in Amnestic and Non-amnestic Patients With Mild Cognitive Impairment: Preliminary Findings From Genotype Variants on Training Effects
Authors: Hernes Susanne S. , Flak Marianne M. , Løhaugen Gro C. C. , Skranes Jon , Hol Haakon R. , Madsen Bengt-Ove , Knapskog Anne-Brita , Engvig Andreas , Pripp Are , Ulstein Ingun , Lona Trine , Zhang Xin , Chang Linda
Published: February 2021

Working memory training (WMT) effects may be modulated by mild cognitive impairment (MCI) subtypes, and variations inAPOE-epsilon (APOE-ε) andLMX1Agenotypes. Sixty-one individuals (41 men/20 women, mean age 66 years) diagnosed with MCI (31 amnestic/30 non-amnestic) and genotyped forAPOE-ε andLMX1Acompleted 4 weeks/20–25 sessions of WMT. Cognitive functions were assessed before, 4 weeks and 16 weeks after WMT. Except for Processing Speed, the non-amnestic MCI group (naMCI) outperformed the amnestic MCI (aMCI) group in all cognitive domains across all time-points. At 4 weeks, working memory function improved in both groups (p< 0.0001), but at 16 weeks the effects only remained in the naMCI group. Better performance was found after training for the naMCI patients withLMX1A-AA genotype and for theAPOE-ε4 carriers. Only the naMCI-APOE-ε4 group showed improved Executive Function at 16 weeks. WMT improved working memory and some non-trained cognitive functions in individuals with MCI. The naMCI group had greater training gain than aMCI group, especially in those withLMX1A-AA genotype and amongAPOE-ε4-carriers. Further research with larger sample sizes for the subgroups and longer follow-up evaluations is warranted.
Upper Motor Neuron Signs in the Cervical Region of Patients With Flail Arm Syndrome
Authors: Xu Yingsheng , Chen Junyi , Zhang Shuo , Fan Dongsheng
Published: February 2021

Objective: We investigated upper motor neuron (UMN) signs in the cervical region in a Chinese clinic-based cohort of patients with flail arm syndrome (FAS) by clinical examination and neurophysiological tests such as triple stimulation technique (TST) and pectoralis tendon reflex testing.

Methods: A total of 130 consecutive FAS patients from Peking University Third Hospital underwent physical examination and neurophysiological tests at baseline and 3 months, 6 months, 9 months, and 12 months later. Pyramidal signs, pectoralis tendon reflex and TST results were evaluated to estimate the function of cervical spinal UMNs.

Results: At the first visit, weakness of the bilateral proximal upper limbs was found in 99 patients, while weakness of a single proximal upper limb was found in 31 patients. There were 49 patients with tendon hyperreflexia, 42 patients with tendon hyporeflexia and 39 patients with tendon areflexia. All except 4 of the patients had brisk pectoralis tendon reflex. The UMN score of the cervical region was 1.7 ± 0.4, and the lower motor neuron score of that region was 3.5 ± 0.3. The TSTtest/TSTcontrol amplitude ratio was 65.7 ± 7.5%. The latency of quantitative detection of the pectoralis tendon reflex was 7.7 ± 1.2 ms. In the follow-up study, the UMN score and the TSTtest/TSTcontrol amplitude ratio decreased, while the lower motor neuron score increased, and the latency of quantitative detection of the pectoralis tendon reflex remained steady.

Conclusion: Although the signs of cervical spinal UMN dysfunction in patients with FAS were often concealed by muscle atrophy in the progression of the disease, TST and pectoralis tendon reflex could reveal it.
Endovascular Therapy for Basilar Arterial Trunk Aneurysms
Authors: Wang Yiheng , Xu Kan , Song Jia , Yu Jinlu
Published: February 2021

Background: Although aneurysms rarely occur in the basilar artery (BA) trunk, the majority of those that do are dissection aneurysms. Currently, the mainstream therapy for BA trunk aneurysms is endovascular therapy (EVT), which mainly includes single coiling or conventional low-metal-coverage stent-assisted EVT, but the efficacy remains to be evaluated.

Methods: A retrospective study was performed for the patients who were admitted to our institution for BA trunk aneurysms and underwent EVT. A total of 28 patients were collected in this study.

Results: The patients were aged 23–71 years (53.7 ± 11.5 years on average); nine were female (32.1%, 9/28), and 19 were male (67.9%, 19/28). The patients were given single coiling or conventional low-metal-coverage stent-assisted EVT. Among the 28 patients, 10 (35.7%, 10/28) developed complications, 90% (9/10) of which were ischemic and 10% (1/10) were hemorrhagic. Among the 28 patients, 5 (17.9%, 5/28) died. The surviving 23 patients (82.1%, 23/28) recovered well.

Conclusions: This study found that for BA trunk aneurysms, single coiling or conventional low-metal-coverage stent-assisted EVT still had some risks. The risks are mainly from brainstem ischemia. Therefore, the perforators of the BA trunk must be carefully evaluated and prevented from receiving damage from the EVT procedure. This study also shows that 82.1% of patients recovered well. Therefore, EVT can result in an acceptable prognosis.
Common and Specific Alterations of Amygdala Subregions in Major Depressive Disorder With and Without Anxiety: A Combined Structural and Resting-State Functional MRI Study
Authors: Li Yao Yao , Ni Xiao kang , You Ya feng , Qing Yan hua , Wang Pei rong , Yao Jia shu , Ren Ke ming , Zhang Lei , Liu Zhi wei , Song Tie jun , Wang Jinhui , Zang Yu-Feng , Shen Yue di , Chen Wei
Published: February 2021

Anxious major depressive disorder is a common subtype of major depressive disorder; however, its unique neural mechanism is not well-understood currently. Using multimodal MRI data, this study examined common and specific alterations of amygdala subregions between patients with and without anxiety. No alterations were observed in the gray matter volume or intra-region functional integration in either patient group. Compared with the controls, both patient groups showed decreased functional connectivity between the left superficial amygdala and the left putamen, and between the right superficial amygdala and the bilateral anterior cingulate cortex and medial orbitofrontal cortex, while only patients with anxiety exhibited decreased activity in the bilateral laterobasal and superficial amygdala. Moreover, the decreased activity correlated negatively with the Hamilton depression scale scores in the patients with anxiety. These findings provided insights into the pathophysiologic processes of anxious major depressive disorder and may help to develop new and effective treatment programs.
Insights Into the Mechanism of Tyrosine Nitration in Preventing β-Amyloid Aggregation in Alzheimer’s Disease
Authors: Zhao Jie , Shi Qihui , Zheng Ye , Liu Qiulian , He Zhijun , Gao Zhonghong , Liu Qiong
Published: February 2021

Nitration of tyrosine at the tenth residue (Tyr10) in amyloid-β (Aβ) has been reported to reduce its aggregation and neurotoxicity in our previous studies. However, the exact mechanism remains unclear. Here, we used Aβ1–42 peptide with differently modified forms at Tyr10 to investigate the molecular mechanism to fill this gap. By using immunofluorescent assay, we confirmed that nitrated Aβ was found in the cortex of 10-month-old female triple transgenic mice of Alzheimer’s disease (AD). And then, we used the surface-enhanced Raman scattering (SERS) method and circular dichroism (CD) to demonstrate that the modification and mutation of Tyr10 in Aβ have little impact on conformational changes. Then, with the aids of fluorescence assays of thioflavin T and 4,4′-dianilino-1,1′-binaphthyl-5,5′-disulfonic acid, transmission electron microscopy (TEM), atomic force microscopy (AFM), and dynamic light scattering (DLS), we found that adding a large group to the phenolic ring of Tyr10 of Aβ could not inhibit Aβ fibrilization and aggregation. Nitration of Aβ reduces its aggregation mainly because it could induce the deprotonation of the phenolic hydroxyl group of Tyr10 of Aβ at physiological pH. We proposed that the negatively charged Tyr10 caused by nitration at physiological pH could interact with the salt bridge between Glu11 and His6 or His13 and block the kink around Tyr10, thereby preventing Aβ fibrilization and aggregation. These findings provide us new insights into the relationship between Tyr10 nitration and Aβ aggregation, which would help to further understand that keeping the balance of nitric oxide in vivo is important for preventing AD.
Six Weeks of Aerobic Exercise in Untrained Men With Overweight/Obesity Improved Training Adaptations, Performance and Body Composition Independent of Oat/Potato or Milk Based Protein-Carbohydrate Drink Supplementation
Authors: Pettersson Stefan , Edin Fredrik , Hjelte Carl , Scheinost David , Wagner Sandro , Ekblom Björn , Jessen Niels , Madsen Klavs , Andersson-Hall Ulrika
Published: February 2021

Background: Protein availability around aerobic exercise might benefit aerobic capacity and body composition in normal weight adults. However, it is unknown if individuals with overweight/obesity elicit similar adaptations or improve other cardiometabolic/health-related markers in response to different types of protein. Thus, our aim was to study the effect of supplementation of two different protein drinks in conjunction with exercise on aerobic capacity, body composition and blood health markers in untrained subjects with overweight or obesity.

Methods: The present study measured training adaptation and health parameters over a 6 week period in untrained men with overweight/obesity (n = 28; BMI 30.4 ± 2.2 kg/m2) ingesting either plant- (Oat/Potato; n = 8) or animal-based (Milk; n = 10) protein-carbohydrate drinks (10 g of protein/serving), or a control carbohydrate drink (n = 10) acutely before and after each training session (average three sessions/week @ 70% HRmax). Pre-post intervention V˙O2peak, muscle biopsies and blood samples were collected, body composition measured (DXA) and two different exercise tests performed. Body weight was controlled with participants remaining weight stable throughout the intervention.

Results: For the groups combined, the training intervention significantly increased V˙O2peak (8%; P < 0.001), performance in a time-to-exhaustion trial (~ 100%; P < 0.001), mitochondrial protein content and enzyme activity (~20–200%). Lean body mass increased (1%; P < 0.01) and fat mass decreased (3%; P < 0.01). No significant effects on fasting blood glucose, insulin, lipids or markers of immune function were observed. There were no significant interactions between drink conditions for training adaptation or blood measurements. For body composition, the Oat/Potato and carbohydrate group decreased leg fat mass significantly more than the Milk group (interaction P < 0.05).

Conclusions: Aerobic capacity and body composition were improved and a number of mitochondrial, glycolytic and oxidative skeletal muscle proteins and enzyme activities were upregulated by a 6 week training intervention. However, none of the parameters for endurance training adaptation were influenced by protein supplementation before and after each training session.
A Phase II, Single-Arm Study of Apatinib and Oral Etoposide in Heavily Pre-Treated Metastatic Breast Cancer
Authors: Hu Nanlin , Zhu Anjie , Si Yiran , Yue Jian , Wang Xue , Wang Jiayu , Ma Fei , Xu Binghe , Yuan Peng
Published: February 2021

Introduction

We performed this clinical trial to evaluate the efficacy and safety of apatinib and oral etoposide in patients with HER2-negative locally advanced or metastatic breast cancer (MBC).

Methods

Patients with HER2-negative MBC previously treated with anthracycline and taxanes and failed ≥1 prior chemotherapy regimens were recruited. The starting dose of apatinib was 500 and 425 mg in patients with ECOG scores of 0–1 and 2, respectively. The etoposide capsules were given at 50 mg/m2 on days 1 to 10 for 21 days. The primary end point was objective response rate (ORR). Secondary end points included progression-free survival (PFS), disease control rate (DCR), overall survival (OS), and safety.

Results

Thirty-one eligible patients were enrolled. The median follow-up time was 11 months. The median PFS for all patients was 6.9 months [95% confidence interval (CI) 6.0–7.9], and 6.9 months (95% CI 5.3–8.6) and 6.6 months (95% CI 1.4–11.7) for patients with apatinib 425 and 500mg once daily, respectively. The ORR was 35.5% (11/31). The DCR was 87.1% (27/31). The median OS was 20.4 months (95% CI 11.4–29.3). The median PFS of patients who had hypertension and proteinuria was longer than that for those without hypertension and proteinuria. The most common grade 3/4 treatment-related AEs were hypertension (12/31, 38.7%), fatigue (3/31, 9.7%), thrombocytopenia (3/31, 9.7%).

Conclusion

Apatinib combined with etoposide capsules is effective and tolerable in heavily pretreated, metastatic HER2-negative breast cancer patients. A lower apatinib dose provide equivalent efficacy and reduced toxicity.

Clinical Trial Registration

https://clinicaltrials.gov/, identifier NCT03535961.