bluuebunny/crossref_metadata_2025 huggingface dataset:
Hepatocyte Endoplasmic Reticulum Stress Inhibits Hepatitis B Virus Secretion and Delays Intracellular Hepatitis B Virus Clearance After Entecavir Treatment
Authors: Chen Huan , Mu Maoyuan , Liu Qichuan , Hu Han , Tian Caiyun , Zhang Guoyuan , Li Ying , Yang Fangwan , Lin Shide
Published: February 2021

Background: The aim of this study was to explore the effects of endoplasmic reticulum (ER) stress on hepatitis B virus (HBV) replication and the antiviral effect of entecavir (ETV).

Methods: Thapsigargin (TG) and stearic acid (SA) were used to induce ER stress in HepG2.2.15 cells and HepAD38 cells that contained an integrated HBV genome, while ETV was used to inhibit HBV replication. The expression levels of glucose-regulated protein 78 (GRP78) and phosphorylated eukaryotic translation initiation factor 2 subunit alpha (p-eIF2α) were measured by western blotting. Intracellular HBV DNA was determined by qPCR; HBsAg by western blotting; HBV RNA by real-time RT-qPCR; HBsAg and HBeAg in supernatants by enzyme-linked immunosorbent assay (ELISA); and HBV DNA in supernatants by qPCR.

Results: TG and SA induced ER stress in HepG2.2.15 cells and HepAD38 cells from 12 to 48 h post treatment. However, 4-phenylbutyric acid (PBA) partly alleviated the TG-induced ER stress. Moreover, TG inhibited HBsAg, HBeAg, and HBV DNA secretion from 12 to 48 h, while different concentrations of SA inhibited HBsAg and HBV DNA secretion at 48 h. TG promoted intracellular HBV DNA and HBsAg accumulation and the transcription of the HBV 3.5-kb mRNA and S mRNA. PBA treatment restored the secretion of HBsAg and HBV DNA. Finally, ER stress accelerated extracellular HBV DNA clearance but delayed intracellular HBV DNA clearance after ETV treatment.

Conclusions: Hepatocyte ER stress promoted intracellular HBV DNA and HBsAg accumulation by inhibiting their secretion. Our study also suggested that hepatocyte ER stress delayed intracellular HBV DNA clearance after ETV treatment.
Airway Clearance Techniques: The Right Choice for the Right Patient
Authors: Belli Stefano , Prince Ilaria , Savio Gloria , Paracchini Elena , Cattaneo Davide , Bianchi Manuela , Masocco Francesca , Bellanti Maria Teresa , Balbi Bruno
Published: February 2021

The management of bronchial secretions is one of the main problems encountered in a wide spectrum of medical conditions ranging from respiratory disorders, neuromuscular disorders and patients undergoing either thoracic or abdominal surgery. The purpose of this review is illustrate to the reader the different ACTs currently available and the related evidence present in literature. Alongside methods with a strong background behind as postural drainage, manual techniques or PEP systems, the current orientation is increasingly aimed at devices that can mobilize and / or remove secretions. Cough Assist, Vacuum Techniques, systems that modulate airflow have more and more scientific evidence. Different principles combination is a new field of investigation that goes toward an increasing of clinical complexity that will facing us.
Exploring the Prevalence and Factors Associated With Fatigue in Axial Spondyloarthritis in an Asian Cohort in Singapore
Authors: Lim Wei Ze , Fong Warren , Kwan Yu Heng , Leung Ying Ying
Published: February 2021

Aim:To evaluate the prevalence of fatigue and the factors associated with fatigue among patients with axial spondyloarthritis (axSpA) within an Asian population.

Method:We used the baseline data from a clinic registry in a tertiary referral center. All patients fulfilled the 2009 Assessment of SpondyloArthritis international Society (ASAS) classification criteria for axSpA. Severe fatigue was defined as Bath Ankylosing Spondylitis Disease Activity Index-fatigue (BASDAI-fatigue) ≥5/10 and vitality domain of Short Form-36 Health Survey (SF-36 VT) ≤10th percentile of the general population.

Results:We included 262 consecutive patients with axSpA (79% men, 82.4% Chinese). The mean (standard deviation, SD) age and duration of disease were 41.7 (13.7) and 10.1 (8.3) years, respectively. 145 (55.3%) and 52 (31.1%) patients reported severe fatigue by the BASDAI-fatigue and SF-36 VT criteria, respectively. Patients with severe fatigue had worse scores across all disease activity assessments and disease impact measures compared to those without severe fatigue. Using principal component analyses, disease activity and impact were associated with BASDAI-fatigue, while disease activity and impact, and disease chronicity were associated with SF-36 VT. In the univariable analyses, all disease activity assessments and disease impact measures correlated with both BASDAI-fatigue and SF-36 VT. In the multivariable analyses, BASDAI-axial pain, BASFI, BAS-G, and ethnicity were associated with BASDAI-fatigue, while ASQoL and BASDAI-morning stiffness were associated with SF-36 VT.

Conclusion:Fatigue is prevalent amongst patients with axSpA in Asia and is associated with disease activity, disease impact as well as patient related factors.
Antibiotic Potential and Biophysical Characterization of Amphipathic β-Stranded [XZ]n Peptides With Alternating Cationic and Hydrophobic Residues
Authors: Strandberg Erik , Wadhwani Parvesh , Ulrich Anne S.
Published: February 2021

Cationic membrane-active peptides are considered to be promising candidates for antibiotic treatment. Many natural and artificial sequences show an antimicrobial activity when they are able to take on an amphipathic fold upon membrane binding, which in turn perturbs the integrity of the lipid bilayer. Most known structures are α-helices and β-hairpins, but also cyclic knots and other irregular conformations are known. Linear β-stranded antimicrobial peptides are not so common in nature, but numerous model sequences have been designed. Interestingly, many of them tend to be highly membranolytic, but also have a significant tendency to self-assemble into β-sheets by hydrogen-bonding. In this minireview we examine the literature on such amphipathic peptides consisting of simple repetitive sequences of alternating cationic and hydrophobic residues, and discuss their advantages and disadvantages. Their interactions with lipids have been characterized with a number of biophysical techniques—especially circular dichroism, fluorescence, and infrared—in order to determine their secondary structure, membrane binding, aggregation tendency, and ability to permeabilize vesicles. Their activities against bacteria, biofilms, erythrocytes, and human cells have also been studied using biological assays. In line with the main scope of this Special Issue, we attempt to correlate the biophysical results with the biological data, and in particular we discuss which properties (length, charge, aggregation tendency, etc.) of these simple model peptides are most relevant for their biological function. The overview presented here offers ideas for future experiments, and also suggests a few design rules for promising β-stranded peptides to develop efficient antimicrobial agents.
A Live Attenuated H9N2 Avian Influenza Vaccine Prevents the Viral Reassortment by Exchanging the HA and NS1 Packaging Signals
Authors: Chen Sujuan , Quan Keji , Wang Hui , Li Shi , Xue Jing , Qin Tao , Chu Dianfeng , Fan Gencheng , Du Yuanzhao , Peng Daxin
Published: February 2021

The H9N2 avian influenza virus is not only an important zoonotic pathogen, it can also easily recombine with other subtypes to generate novel reassortments, such as the H7N9 virus. Although H9N2 live attenuated vaccines can provide good multiple immunities, including humoral, cellular, and mucosal immunity, the risk of reassortment between the vaccine strain and wild-type virus is still a concern. Here, we successfully rescued an H9N2 live attenuated strain [rTX-NS1-128 (mut)] that can interdict reassortment, which was developed by exchanging the mutual packaging signals of HA and truncated NS1 genes and confirmed by RT-PCR and sequencing. The dynamic growth results showed that rTX-NS1-128 (mut) replication ability in chick embryos was not significantly affected by our construction strategy compared to the parent virus rTX strain. Moreover, rTX-NS1-128 (mut) had good genetic stability after 15 generations and possessed low pathogenicity and no contact transmission characteristics in chickens. Furthermore, chickens were intranasally immunized by rTX-NS1-128 (mut) with a single dose, and the results showed that the hemagglutination inhibition (HI) titers peaked at 3 weeks after vaccination and lasted at least until 11 weeks. The cellular immunity (IL-6 and IL-12) and mucosal immunity (IgA and IgG) in the nasal and trachea samples were significantly increased compared to inactivated rTX. Recombinant virus provided a good cross-protection against homologous TX strain (100%) and heterologous F98 strain (80%) challenge. Collectively, these data indicated that rTX-NS1-128(mut) lost the ability for independent reassortment of HA and NS1-128 and will be expected to be used as a potential live attenuated vaccine against H9N2 subtype avian influenza.
Translating New Synthetic Biology Advances for Biosensing Into the Earth and Environmental Sciences
Authors: Del Valle Ilenne , Fulk Emily M. , Kalvapalle Prashant , Silberg Jonathan J. , Masiello Caroline A. , Stadler Lauren B.
Published: February 2021

The rapid diversification of synthetic biology tools holds promise in making some classically hard-to-solve environmental problems tractable. Here we review longstanding problems in the Earth and environmental sciences that could be addressed using engineered microbes as micron-scale sensors (biosensors). Biosensors can offer new perspectives on open questions, including understanding microbial behaviors in heterogeneous matrices like soils, sediments, and wastewater systems, tracking cryptic element cycling in the Earth system, and establishing the dynamics of microbe-microbe, microbe-plant, and microbe-material interactions. Before these new tools can reach their potential, however, a suite of biological parts and microbial chassis appropriate for environmental conditions must be developed by the synthetic biology community. This includes diversifying sensing modules to obtain information relevant to environmental questions, creating output signals that allow dynamic reporting from hard-to-image environmental materials, and tuning these sensors so that they reliably function long enough to be useful for environmental studies. Finally, ethical questions related to the use of synthetic biosensors in environmental applications are discussed.
Effect of Long-Term Fertilization on Ammonia-Oxidizing Microorganisms and Nitrification in Brown Soil of Northeast China
Authors: Cai Fangfang , Luo Peiyu , Yang Jinfeng , Irfan Muhammad , Zhang Shiyu , An Ning , Dai Jian , Han Xiaori
Published: February 2021

The objective of this study was to find out changes in ammonia oxidation microorganisms with respect to fertilizer as investigated by real-time polymerase chain reaction and high-throughput sequencing. The treatments included control (CK); chemical fertilizer nitrogen low (N) and high (N2); nitrogen and phosphorus (NP); nitrogen phosphorus and potassium (NPK) and organic manure fertilizer (M); MN; MN2; MNPK. The results showed that long-term fertilization influenced soil fertility and affected the abundance and community of ammonia-oxidizing microorganisms by changing the physical and chemical properties of the soil. The abundance and community structure of ammonia-oxidizing archaea (AOA) and ammonia-oxidizing bacteria (AOB) was influenced by soil organic carbon, total nitrogen, total soil phosphorus, available phosphorus, available potassium, and soil nitrate. Soil environmental factors affected the nitrification potential by affecting the structure of ammonia-oxidizing microorganisms; specific and rare AOA and AOB rather than the whole AOA or AOB community played dominant role in nitrification.
Reactive Oxygen Species in Pathogen Clearance: The Killing Mechanisms, the Adaption Response, and the Side Effects
Authors: Li Hao , Zhou Xuedong , Huang Yuyao , Liao Binyou , Cheng Lei , Ren Biao
Published: February 2021

Reactive oxygen species (ROS) are attractive weapons in both antibiotic-mediated killing and host-mediated killing. However, the involvement of ROS in antibiotic-mediated killing and complexities in host environments challenge the paradigm. In the case of bacterial pathogens, the examples of some certain pathogens thriving under ROS conditions prompt us to focus on the adaption mechanism that pathogens evolve to cope with ROS. Based on these, we here summarized the mechanisms of ROS-mediated killing of either antibiotics or the host, the examples of bacterial adaption that successful pathogens evolved to defend or thrive under ROS conditions, and the potential side effects of ROS in pathogen clearance. A brief section for new antibacterial strategies centered around ROS was also addressed.
Role of cpxA Mutations in the Resistance to Aminoglycosides and β-Lactams in Salmonella enterica serovar Typhimurium
Authors: Jing Wenxian , Liu Juan , Wu Shanshan , Li Xuerui , Liu Yongsheng
Published: February 2021

Although it has been reported that deletion of the response regulator, CpxR, in the CpxRA system confers sensitivity to aminoglycosides (AGAs) and β-lactams in Salmonella enterica serovar Typhimurium, the regulatory effects of CpxA on multidrug resistance (MDR) are yet to be fully investigated in this organism. Here, to explore the role of CpxA in MDR, various cpxA mutants including a null mutant (JSΔcpxA), a site-directed mutant (JSΔcpxA38) and an internal in-frame deletion mutant (JSΔcpxA92–104) of the S. enterica serovar Typhimurium strain JS, were constructed. It was revealed that cpxA and cpxR deletion mutants have opposing roles in the regulation of resistance to AGAs and β-lactams. Amikacin and cefuroxime can activate the CpxRA system, which results in increased resistance of the wild-type compared with the cpxR deletion mutant. All the cpxA mutations significantly increased resistance to AGAs and β-lactams due to CpxRA system activation via the phosphorylation of CpxR. Moreover, AckA-Pta-dependent activation of CpxR increased the antibiotic resistance of cpxA deletion mutants. Further research revealed that the AcrAB-TolC conferred resistance to some AGAs and β-lactams but does not influence the regulation of resistance by CpxRA against these antibiotics. The detection of candidate MDR-related CpxR regulons revealed that the mRNA expression levels of spy, ycca, ppia, htpX, stm3031, and acrD were upregulated and that of ompW was downregulated in various cpxA mutants. Furthermore, the expression levels of nuoA and sdhC mRNAs were downregulated only in JSΔcpxA92–104. These results suggested that cpxA mutations contribute to AGAs and β-lactams resistance, which is dependent on CpxR.
Evolution of Drug-Resistant Mycobacterium tuberculosis Strains and Their Adaptation to the Human Lung Environment
Authors: Allué-Guardia Anna , García Juan I. , Torrelles Jordi B.
Published: February 2021

In the last two decades, multi (MDR), extensively (XDR), extremely (XXDR) and total (TDR) drug-resistantMycobacterium tuberculosis(M.tb) strains have emerged as a threat to public health worldwide, stressing the need to develop new tuberculosis (TB) prevention and treatment strategies. It is estimated that in the next 35 years, drug-resistant TB will kill around 75 million people and cost the global economy $16.7 trillion. Indeed, the COVID-19 pandemic alone may contribute with the development of 6.3 million new TB cases due to lack of resources and enforced confinement in TB endemic areas. Evolution of drug-resistantM.tbdepends on numerous factors, such as bacterial fitness, strain’s genetic background and its capacity to adapt to the surrounding environment, as well as host-specific and environmental factors. Whole-genome transcriptomics and genome-wide association studies in recent years have shed some insights into the complexity ofM.tbdrug resistance and have provided a better understanding of its underlying molecular mechanisms. In this review, we will discussM.tbphenotypic and genotypic changes driving resistance, including changes in cell envelope components, as well as recently described intrinsic and extrinsic factors promoting resistance emergence and transmission. We will further explore how drug-resistantM.tbadapts differently than drug-susceptible strains to the lung environment at the cellular level, modulatingM.tb–host interactions and disease outcome, and novel next generation sequencing (NGS) strategies to study drug-resistant TB.
Persistence of Hepatitis A Virus RNA in Water, on Non-porous Surfaces, and on Blueberries
Authors: Trudel-Ferland Mathilde , Jubinville Eric , Jean Julie
Published: February 2021

Enteric viruses, such as human norovirus and hepatitis A virus (HAV), are the leading cause of transmissible foodborne illness. Fresh produce such as berries are often contaminated by infected food handlers, soiled water, or food contact surfaces. The gold-standard method for virus detection throughout the food chain is RT-qPCR, which detects portions of genomes including non-infectious viral particles and naked viral RNA. The aim of this study was to evaluate the persistence of heat-inactivated HAV in water, phosphate-buffered saline, on stainless steel and polyvinyl chloride, and on blueberries at −80°C, −20°C, 4°C, and room temperature. In water and phosphate-buffered saline, viral RNA could be detected for up to 90 days regardless of temperature when the initial load was 2.5 × 104 or 2.5 × 106 genome copies. It was detected on polyvinyl chloride and blueberries under most conditions. On stainless steel, the large initial load persisted for 90 days, while the medium-level load was detected only up to 16 days at room temperature or 60 days at 4°C. The detection of non-infectious viral RNA can confound investigations of gastroenteritis outbreaks. Pretreatments that discriminate between naked RNA, non-infectious virions and infectious virions need to be included in the RT-qPCR method in order to reduce the risk of positive results associated with non-infectious viral particles.
The Orientia tsutsugamushi ScaB Autotransporter Protein Is Required for Adhesion and Invasion of Mammalian Cells
Authors: Nguyen Yen Thi Hai , Kim Chaewon , Kim Yuri , Jeon Kyeongseok , Kim Hong-il , Ha Na-Young , Cho Nam-Hyuk
Published: February 2021

Autotransporter proteins are widely present in Gram-negative bacteria. They play a pivotal role in processes related to bacterial pathogenesis, including adhesion, invasion, colonization, biofilm formation, and cellular toxicity. Bioinformatics analysis revealed that Orientia tsutsugamushi, the causative agent of scrub typhus, encodes six different autotransporter genes (scaA–scaF). Although four of these genes (scaA, scaC, scaD, and scaE) are present in diverse strains, scaB and scaF have been detected in only a limited number of strains. Previous studies have demonstrated that ScaA and ScaC are involved in the adherence of host cells. However, the putative function of other O. tsutsugamushi Sca proteins has not been studied yet. In this study, we show that scaB is transcribed and expressed on the surface of O. tsutsugamushi Boryong strain. Using a heterologous Escherichia coli expression system, we demonstrated that ScaB-expressing E. coli can successfully mediate adherence to and invasion into non-phagocytic cells, including epithelial and endothelial cells. In addition, pretreatment with a recombinant ScaB polypeptide inhibits the entry of O. tsutsugamushi into cultured mammalian cells. Finally, we also identified the scaB gene in the Kuroki and TA686 strains and observed high levels of sequence variation in the passenger domains. Here, we propose that the ScaB protein of O. tsutsugamushi can mediate both adhesion to and invasion into host cells in the absence of other O. tsutsugamushi genes and may play important roles in bacterial pathogenesis.
One-Step Reverse-Transcription Recombinase Polymerase Amplification Using Lateral Flow Strips for the Detection of Coxsackievirus A6
Authors: Xie Jia , Yang Xiaohan , Duan Lei , Chen Keyi , Liu Pan , Zhan Wenli , Zhang Changbin , Zhao Hongyu , Wei Mengru , Tang Yuan , Luo Mingyong
Published: February 2021

Hand, foot, and mouth disease (HFMD) is a common infectious disease affecting mainly children under 5 years of age. Coxsackievirus A6 (CVA-6), a major causative pathogen of HFMD, has caused outbreaks in recent years. Currently, no effective vaccine or antiviral treatments are available. In this study, one-step reverse-transcription recombinase polymerase amplification (RT-RPA), combined with a disposable lateral flow strip (LFS) assay, was developed to detect CVA-6. This assay can be performed in less than 35 min at 37°C without expensive instruments, and the result can be observed directly with the naked eye. The sensitivity of the RT-RPA-LFS was 10 copies per reaction, which was comparable to that of the conventional real-time quantitative polymerase chain reaction (qPCR) assays. Moreover, the assay specificity was 100%. The clinical performance of the RT-RPA-LFS assay was evaluated using 142 clinical samples, and the coincidence rate between RT-RPA-LFS and qPCR was 100%. Therefore, our RT-RPA-LFS assay provides a simple and rapid approach for point-of-care CVA-6 diagnosis.
Eradication of Helicobacter pylori and Gastric Cancer: A Controversial Relationship
Authors: Piscione Mariagrazia , Mazzone Mariangela , Di Marcantonio Maria Carmela , Muraro Raffaella , Mincione Gabriella
Published: February 2021

Worldwide, gastric cancer (GC) represents the fifth cancer for incidence, and the third as cause of death in developed countries. Indeed, it resulted in more than 780,000 deaths in 2018. Helicobacter pylori appears to be responsible for the majority of these cancers. On the basis of recent studies, and either alone or combined with additional etiological factors, H. pylori is considered a “type I carcinogen.” Over recent decades, new insights have been obtained into the strategies that have been adopted by H. pylori to survive the acidic conditions of the gastric environment, and to result in persistent infection, and dysregulation of host functions. The multistep processes involved in the development of GC are initiated by transition of the mucosa into chronic non-atrophic gastritis, which is primarily triggered by infection with H. pylori. This gastritis then progresses into atrophic gastritis and intestinal metaplasia, and then to dysplasia, and following Correa’s cascade, to adenocarcinoma. The use of antibiotics for eradication of H. pylori can reduce the incidence of precancerous lesions only in the early stages of gastric carcinogenesis. Here, we first survey the etiology and risk factors of GC, and then we analyze the mechanisms underlying tumorigenesis induced by H. pylori, focusing attention on virulence factor CagA, inflammation, oxidative stress, and ErbB2 receptor tyrosine kinase. Moreover, we investigate the relationships between H. pylori eradication therapy and other diseases, considering not only cardia (upper stomach) cancers and Barrett’s esophagus, but also asthma and allergies, through discussion of the “hygiene hypothesis. ” This hypothesis suggests that improved hygiene and antibiotic use in early life reduces microbial exposure, such that the immune response does not become primed, and individuals are not protected against atopic disorders, asthma, and autoimmune diseases. Finally, we overview recent advances to uncover the complex interplay between H. pylori and the gut microbiota during gastric carcinogenesis, as characterized by reduced bacterial diversity and increased microbial dysbiosis. Indeed, it is of particular importance to identify the bacterial taxa of the stomach that might predict the outcome of gastric disease through the stages of Correa’s cascade, to improve prevention and therapy of gastric carcinoma.
Membrane Rafts: Portals for Viral Entry
Authors: Ripa Inés , Andreu Sabina , López-Guerrero José Antonio , Bello-Morales Raquel
Published: February 2021

Membrane rafts are dynamic, small (10–200 nm) domains enriched with cholesterol and sphingolipids that compartmentalize cellular processes. Rafts participate in roles essential to the lifecycle of different viral families including virus entry, assembly and/or budding events. Rafts seem to participate in virus attachment and recruitment to the cell surface, as well as the endocytic and non-endocytic mechanisms some viruses use to enter host cells. In this review, we will introduce the specific role of rafts in viral entry and define cellular factors implied in the choice of one entry pathway over the others. Finally, we will summarize the most relevant information about raft participation in the entry process of enveloped and non-enveloped viruses.
Pollen Streptomyces Produce Antibiotic That Inhibits the Honey Bee Pathogen Paenibacillus larvae
Authors: Grubbs Kirk J. , May Daniel S. , Sardina Joseph A. , Dermenjian Renee K. , Wyche Thomas P. , Pinto-Tomás Adrián A. , Clardy Jon , Currie Cameron R.
Published: February 2021

Humans use natural products to treat disease; similarly, some insects use natural products produced by Actinobacteria to combat infectious pathogens. Honey bees, Apis mellifera, are ecologically and economically important for their critical role as plant pollinators and are host to diverse and potentially virulent pathogens that threaten hive health. Here, we provide evidence that Actinobacteria that can suppress pathogenic microbes are associated with A. mellifera. We show through culture-dependent approaches that Actinobacteria in the genus Streptomyces are commonly isolated from foraging bees, and especially common in pollen stores. One strain, isolated from pollen stores, exhibited pronounced inhibitory activity against Paenibacillus larvae, the causative agent of American foulbrood. Bioassay-guided HPLC fractionation, followed by NMR and mass spectrometry, identified the known macrocyclic polyene lactam, piceamycin that was responsible for this activity. Further, we show that in its purified form, piceamycin has potent inhibitory activity toward P. larvae. Our results suggest that honey bees may use pollen-derived Actinobacteria and their associated small molecules to mediate colony health. Given the importance of honey bees to modern agriculture and their heightened susceptibility to disease, the discovery and development of antibiotic compounds from hives could serve as an important strategy in supporting disease management within apiaries.
The Role of Pseudo-Orthocaspase (SyOC) of Synechocystis sp. PCC 6803 in Attenuating the Effect of Oxidative Stress
Authors: Lema A Saul , Klemenčič Marina , Völlmy Franziska , Altelaar Maarten , Funk Christiane
Published: February 2021

Caspases are proteases, best known for their involvement in the execution of apoptosis—a subtype of programmed cell death, which occurs only in animals. These proteases are composed of two structural building blocks: a proteolytically active p20 domain and a regulatory p10 domain. Although structural homologs appear in representatives of all other organisms, their functional homology, i.e., cell death depending on their proteolytical activity, is still much disputed. Additionally, pseudo-caspases and pseudo-metacaspases, in which the catalytic histidine-cysteine dyad is substituted with non-proteolytic amino acid residues, were shown to be involved in cell death programs. Here, we present the involvement of a pseudo-orthocaspase (SyOC), a prokaryotic caspase-homolog lacking the p10 domain, in oxidative stress in the model cyanobacterium Synechocystis sp. PCC 6803. To study the in vivo impact of this pseudo-protease during oxidative stress its gene expression during exposure to H2O2 was monitored by RT-qPCR. Furthermore, a knock-out mutant lacking the pseudo-orthocaspase gene was designed, and its survival and growth rates were compared to wild type cells as well as its proteome. Deletion of SyOC led to cells with a higher tolerance toward oxidative stress, suggesting that this protein may be involved in a pro-death pathway.
Anticancer Compounds Based on Isatin-Derivatives: Strategies to Ameliorate Selectivity and Efficiency
Authors: Ferraz de Paiva Raphael Enoque , Vieira Eduardo Guimarães , Rodrigues da Silva Daniel , Wegermann Camila Anchau , Costa Ferreira Ana Maria
Published: February 2021

In this review we compare and discuss results of compounds already reported as anticancer agents based on isatin-derivatives, metalated as well as non-metallated. Isatin compounds can be obtained from plants, marine animals, and is also found in human fluids as a metabolite of amino acids. Its derivatives include imines, hydrazones, thiosemicarbazones, among others, already focused on numerous anticancer studies. Some of them have entered in pre-clinical and clinical tests as antiangiogenic compounds or inhibitors of crucial proteins. As free ligands or coordinated to metal ions, such isatin derivatives showed promising antiproliferative properties against different cancer cells, targeting different biomolecules or organelles. Binding to metal ions usually improves its biological properties, indicating a modulation by the metal and by the ligand in a synergistic process. They also reveal diverse mechanisms of action, being able of binding DNA, generating reactive species that cause oxidative damage, and inhibiting selected proteins. Strategies used to improve the efficiency and selectivity of these compounds comprise structural modification of the ligands, metalation with different ions, syntheses of mononuclear and dinuclear species, and use of inserted or anchored compounds in selected drug delivery systems.
Elevated Creatinine Kinase in Peripheral Neuropathy Is Associated With Muscle Cramping
Authors: Jordan Allison , Nagaraj Arun , Hoyle J. Chad , Stino Amro Maher , Arnold W. David , Elsheikh Bakri
Published: February 2021

Introduction: Serum Creatinine Kinase (CK) is a non-specific marker of muscle damage. There has been limited investigation of the association between peripheral neuropathy and CK elevation (hyperCKemia).

Methods: We performed a chart review to investigate the CK level in peripheral neuropathies. Demographics, clinical history, physical exam, electrodiagnostic data, CK level, statin use, etiology of neuropathy, and concomitant neuromuscular disorders were recorded. HyperCKemia was defined using our laboratory cutoff values of >180 U/L (women) and >220 U/L (men).

Results: We identified 450 patients with peripheral neuropathy who had CK testing, 92 (20.4%) of whom had hyperCKemia. Sixty-one of those patients (13.5% of the total figure) had a concomitant etiology that could explain the CK elevation. Thirty-one patients (6.9%) had no other identifiable etiology for their hyperCKemia beyond the neuropathy. The average CK level in the latter cohort with hyperCKemia was 376 U/L (women: 312 U/L; men: 444 U/L). The frequency of cramping was greater in patients with elevated vs. normal CK (p < 0.0001).

Discussion: HyperCKemia can occur in patients with peripheral neuropathy and appears to associate with cramping.
The Role of Frontal Assessment Battery and Frontal Lobe Single-Photon Emission Computed Tomography in the Differential Diagnosis of Progressive Supranuclear Palsy Variants and Corticobasal Syndrome—A Pilot Study
Authors: Alster Piotr , Migda Bartosz , Madetko Natalia , Duszyńska-Wąs Karolina , Drzewińska Agnieszka , Charzyńska Ingeborga , Starczyński Miłosz , Szepelska Ada , Królicki Leszek , Friedman Andrzej
Published: February 2021

Progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS) are clinical syndromes classified as atypical parkinsonism. Due to their overlapping symptomatology, recent research shows the necessity of finding new methods of examination of these clinical entities. PSP is a heterogenic disease. PSP Richardson-Steele Syndrome (PSP-RS) and parkinsonism predominant (PSP-P) are the most common clinical variants of progressive supranuclear palsy syndrome. The different clinical course and life expectancy of PSP-RS and PSP-P stress the need of efficient examination in the early stages. The aim of the study was to evaluate the possible feasibility of the combined use of frontal assessment battery (FAB) and single-photon emission computed tomography (SPECT) in the differentiation of PSP-RS, PSP-P, and CBS. The findings show that FAB may be interpreted as a possible supplementary tool in the differential diagnosis of PSP-P and PSP-RS. The differences in SPECT are less pronounced. The study does not show any advantages of performing combined frontal SPECT and FAB in the differential examination of PSP and CBS. Moreover, PSP-RS and CBS, in a detailed evaluation of the frontal lobe, do not show any significant differences. This is a relatively small study which, however, highlights the relevant features of clinical examination of these rare entities.
Effects of Caffeine on Brown Adipose Tissue Thermogenesis and Metabolic Homeostasis: A Review
Authors: Van Schaik Lachlan , Kettle Christine , Green Rodney , Irving Helen R. , Rathner Joseph A.
Published: February 2021

The impact of brown adipose tissue (BAT) metabolism on understanding energy balance in humans is a relatively new and exciting field of research. The pathogenesis of obesity can be largely explained by an imbalance between caloric intake and energy expenditure, but the underlying mechanisms are far more complex. Traditional non-selective sympathetic activators have been used to artificially elevate energy utilization, or suppress appetite, however undesirable side effects are apparent with the use of these pharmacological interventions. Understanding the role of BAT, in relation to human energy homeostasis has the potential to dramatically offset the energy imbalance associated with obesity. This review discusses paradoxical effects of caffeine on peripheral adenosine receptors and the possible role of adenosine in increasing metabolism is highlighted, with consideration to the potential of central rather than peripheral mechanisms for caffeine mediated BAT thermogenesis and energy expenditure. Research on the complex physiology of adipose tissue, the embryonic lineage and function of the different types of adipocytes is summarized. In addition, the effect of BAT on overall human metabolism and the extent of the associated increase in energy expenditure are discussed. The controversy surrounding the primary β-adrenoceptor involved in human BAT activation is examined, and suggestions as to the lack of translational findings from animal to human physiology and humanin vitrotoin vivomodels are provided. This review compares and distinguishes human and rodent BAT effects, thus developing an understanding of human BAT thermogenesis to aid lifestyle interventions targeting obesity and metabolic syndrome. The focus of this review is on the effect of BAT thermogenesis on overall metabolism, and the potential therapeutic effects of caffeine in increasing metabolism via its effects on BAT.
Dietary Diversity and Its Contribution in the Etiology of Maternal Anemia in Conflict Hit Mount Cameroon Area: A Cross-Sectional Study
Authors: Jugha Vanessa Tita , Anchang-Kimbi Judith Kuoh , Anchang Juliana Adjem , Mbeng Kennedy Aminde , Kimbi Helen Kuokuo
Published: February 2021

Background: In the Mount Cameroon area, maternal anemia remains a major public health concern. We hypothesized that nutrient inadequacy may account for the level of anemia in pregnancy. Thus, this study examined the relative effect of dietary diversity on maternal anemia in the study area.

Methods: A total of 1,014 consenting pregnant women were enrolled in this cross-sectional study. Information on socio-demographic, antenatal characteristics, malaria and anemia control measures were documented. Dietary diversity (DD) was evaluated using the 24-h recall method and hemoglobin (Hb) levels (g/dl) measured using a portable Hb meter. Malaria parasitaemia was diagnosed by blood microscopy. Anemia status was trimester specific. Logistic regression analysis was used determine predictors of maternal anemia.

Results: Among the pregnant women enrolled, the mean DD score was 3.5±0.8 SD and only 10.4% had adequate dietary diversity. Anemia prevalence was 40.9%. Majority of the women consumed starchy staples (99.3%) while least consumed foods were dairy (4.5%), eggs (8.3%), fruits and vegetable (vitamin A-rich) (8.6%). A significant lower prevalence of anemia was associated with intake of dairy (P < 0.001), animal protein (P = 0.006), vitamin A-rich fruits and vegetables (P < 0.001). Furthermore, mean Hb levels were higher (P < 0.001) among women with diverse diets (12.39 ± 1.34) than in those with less diverse diets (10.85 ± 1.33). Predictors of anemia were as follows: study setting [Odd Ratio (OR) = 1.4, 95% CI: 1.07-1.94], occupation (OR = 1.9, 95% CI: 1.16-3.43), number of clinic visits (OR = 1.9, 95% CI: 1.27-2.91), trimester of pregnancy (OR = 3.2, 95% CI: 1.45-7.38), malaria parasitaemia (OR = 1.8, 95% CI: 1.33-2.68), out of home eating (OR = 1.4, 95% CI: 1.03-2.13), and DD (OR = 9.8, 95% CI: 4.56-20.80). The attributable risk of anemia due to dietary diversity was 82.9%.

Conclusion: In the study area, DD is a major risk factor for maternal anemia. This finding underscores the importance of content specific nutrition education during clinic visits to improve intake of protein and iron-rich food in anemia prevention.
Artificial Intelligence in Decision-Making for Colorectal Cancer Treatment Strategy: An Observational Study of Implementing Watson for Oncology in a 250-Case Cohort
Authors: Aikemu Batuer , Xue Pei , Hong Hiju , Jia Hongtao , Wang Chenxing , Li Shuchun , Huang Ling , Ding Xiaoyi , Zhang Huan , Cai Gang , Lu Aiguo , Xie Li , Li Hao , Zheng Minhua , Sun Jing
Published: February 2021

Background

Personalized and novel evidence-based clinical treatment strategy consulting for colorectal cancer has been available through various artificial intelligence (AI) supporting systems such as Watson for Oncology (WFO) from IBM. However, the potential effects of this supporting tool in cancer care have not been thoroughly explored in real-world studies. This research aims to investigate the concordance between treatment recommendations for colorectal cancer patients made by WFO and a multidisciplinary team (MDT) at a major comprehensive gastrointestinal cancer center.

Methods

In this prospective study, both WFO and the blinded MDT’s treatment recommendations were provided concurrently for enrolled colorectal cancers of stages II to IV between March 2017 and January 2018 at Shanghai Minimally Invasive Surgery Center. Concordance was achieved if the cancer team’s decisions were listed in the “recommended” or “for consideration” classification in WFO. A review was carried out after 100 cases for all non-concordant patients to explain the inconsistency, and corresponding feedback was given to WFO’s database. The concordance of the subsequent cases was analyzed to evaluate both the performance and learning ability of WFO.

Results

Overall, 250 patients met the inclusion criteria and were recruited in the study. Eighty-one were diagnosed with colon cancer and 189 with rectal cancer. The concordances for colon cancer, rectal cancer, or overall were all 91%. The overall rates were 83, 94, and 88% in subgroups of stages II, III, and IV. When categorized by treatment strategy, concordances were 97, 93, 89, 87, and 100% for neoadjuvant, surgery, adjuvant, first line, and second line treatment groups, respectively. After analyzing the main factors causing discordance, relative updates were made in the database accordingly, which led to the concordance curve rising in most groups compared with the initial rates.

Conclusion

Clinical recommendations made by WFO and the cancer team were highly matched for colorectal cancer. Patient age, cancer stage, and the consideration of previous therapy details had a significant influence on concordance. Addressing these perspectives will facilitate the use of the cancer decision-support systems to help oncologists achieve the promise of precision medicine.
Associations of Clinical Characteristics and Etiology With Death in Hospitalized Chinese Children After Spontaneous Intracerebral Hemorrhage: A Single-Center, Retrospective Cohort Study
Authors: Huang Xiaoyan , Cheng Zicheng , Xu Ye , Xia Lingfan , Zhan Zhenxiang , Xu Tong , Cao Yungang , Han Zhao
Published: February 2021

Objective: We retrospectively analyzed clinical characteristics, etiology, and mortality risk factors in pediatric cases of non-traumatic spontaneous intracerebral hemorrhage.

Methods: This study involved children between 29 days and 18 years old with confirmed spontaneous intracerebral hemorrhage based on head CT or MRI at the Second Affiliated Hospital of Wenzhou Medical University and Yuying Children's Hospital from January 2008 to March 2020. Demographic and clinical characteristics, etiology, imaging, and treatment data were collected at baseline. Potential risk factors of in-hospital death were identified using univariate analysis and multivariate logistic regression.

Result: A total of 200 children (126 males, median age 5 years) were included in the study. Clinical symptoms of spontaneous intracerebral hemorrhage were typically non-specific (79.5%). One third of patients (31.1%) had a Glasgow Coma Scale score (GCS) ≤ 8, and nearly two-thirds (60.5%) showed a combination of ventricular hemorrhage or subarachnoid hemorrhage. Supratentorial hemorrhage was more common. Cerebrovascular disease (37.0%) and hematological disease (33.5%) were the most frequent etiologies of spontaneous intracerebral hemorrhage. Most patients (74.5%) received non-surgical treatment, while 25.5% received surgical treatment. After an average of 12 days of treatment, 167 children (83.5%) survived and 33 (16.5%) died. Multivariate logistic regression showed herniation syndrome, and low GCS (≤ 8) to be associated with increased risk of mortality, while hemorrhage due to arteriovenous malformation was associated with lower risk of mortality.

Conclusion: Our data suggest that cerebrovascular disease is the most common cause of spontaneous intracerebral hemorrhage among children, and that arteriovenous malformation is associated with lower risk of death in hospital. Conversely, the presence of herniation syndrome, low GCS (≤ 8) increase risk of in-hospital mortality. Our results underscore the importance of timely imaging and supplementary examinations in cases of suspected spontaneous intracerebral hemorrhage.
Supplemental Insulin-Like Growth Factor-1 and Necrotizing Enterocolitis in Preterm Pigs
Authors: Holgersen Kristine , Gao Xiaoyan , Narayanan Rangaraj , Gaur Tripti , Carey Galen , Barton Norman , Pan Xiaoyu , Muk Tik , Thymann Thomas , Sangild Per Torp
Published: February 2021

Background: Recombinant human IGF-1/binding protein-3 (rhIGF-1/BP-3) is currently tested as a therapy in preterm infants but possible effects on the gut, including necrotizing enterocolitis (NEC), have not been tested. The aim of this study was to evaluate if rhIGF-1/BP-3 supplementation in the first days after birth negatively affects clinical variables like growth, physical activity, blood chemistry and hematology and gut maturation (e.g., intestinal permeability, morphology, enzyme activities, cytokine levels, enterocyte proliferation, NEC lesions), using NEC-sensitive preterm pigs as a model for preterm infants.

Methods: Preterm pigs were given twice daily subcutaneous injections of rhIGF-1/BP-3 or vehicle. Blood was collected for IGF-1 measurements and gut tissue for NEC evaluation and biochemical analyses on day 5.

Results: Baseline circulating IGF-1 levels were low in preterm pigs compared with near-term pigs reared by their mother (<20 vs. 70 ng/ml). Injection with rhIGF-1/BP-3 resulted in increased plasma IGF-1 levels for up to 6 h after injection (>40 ng/mL). rhIGF-1/BP-3 treatment reduced the incidence of severe NEC lesions (7/24 vs.16/24, p = 0.01) and overall NEC severity (1.8 ± 0.2 vs. 2.6 ± 0.3, p < 0.05, with most lesions occurring in colon). In the small intestine, villi length (405 ± 25 vs. 345 ± 33 μm) and activities of the brush border peptidases aminopeptidase N and dipeptidylpeptidase IV were increased in rhIGF-1/BP-3 treated pigs, relative to control pigs (+31–44%, both p < 0.05). The treatment had no effects on body weight, blood chemistry or hematology, except for an increase in blood leucocyte and neutrophil counts (p < 0.05, i.e., reduced neonatal neutropenia). Likewise, rhIGF-1/BP-3 treatment did not affect intestinal tissue cytokine levels (IL-1β, IL-6, IL-8, TNFα,), enterocyte proliferation, goblet cell density, permeability or bacterial translocation to the bone marrow.

Conclusion: Supplemental rhIGF-1/BP-3 did not negatively affect any of the measured variables of clinical status or gut maturation in preterm pigs. Longer-term safety and efficacy of exogenous rhIGF-1/BP-3 to support maturation of the gut and other critical organs in preterm newborns remain to be investigated in both pigs and infants.
CT Angiography or Cardiac MRI for Detection of Coronary Artery Aneurysms in Kawasaki Disease
Authors: van Stijn Diana , Planken Nils , Kuipers Irene , Kuijpers Taco
Published: February 2021

Background: Kawasaki disease (KD) is an acute vasculitis that mainly affects the coronary arteries. This inflammation can cause coronary artery aneurysms (CAAs). Patients with KD need cardiac assessment for risk stratification for the development of myocardial ischemia, based on Z-score (luminal diameter of the coronary artery corrected for body surface area). Echocardiography is the primary imaging modality in KD but has several important limitations. Coronary computed tomographic angiography (cCTA) and Cardiac MRI (CMR) are non-invasive imaging modalities and of additional value for assessment of CAAs with a high diagnostic yield. The objective of this single center, retrospective study is to explore the diagnostic potential of coronary artery assessment of cCTA vs. CMR in children with KD.

Methods and Results: Out of 965 KD patients from our database, a total of 111 cCTAs (104 patients) and 311 CMR (225 patients) have been performed since 2010. For comparison, we identified 54 KD patients who had undergone both cCTA and CMR. CMR only identified eight patients with CAAs compared to 14 patients by cCTA. CMR missed 50% of the CAAs identified by cCTA.

Conclusions: Our single center study demonstrates that cCTA may be a more sensitive diagnostic tool to detect CAAs in KD patients, compared to CMR.
Chemokine Regulation During Epidemic Coronavirus Infection
Authors: Majumdar Shamik , Murphy Philip M.
Published: February 2021

SARS-CoV-2 (Severe Acute Respiratory Syndrome coronavirus-2) is the third coronavirus to emerge as a cause of severe and frequently fatal pneumonia epidemics in humans, joining SARS-CoV and MERS-CoV (Middle East Respiratory Syndrome-coronavirus). As with many infectious diseases, the immune response to coronavirus infection may act as a double-edged sword: necessary for promoting antiviral host defense, but, if not appropriately regulated, also able to incite life-threatening immunopathology. Key immunoregulatory mediators include the chemokines, a large family of leukocyte chemoattractants that coordinate leukocyte infiltration, positioning and activation in infected tissue by acting at specific G protein-coupled receptors. Here, we compare the involvement of chemokines and chemokine receptors during infection with the three epidemic coronaviruses and discuss their potential value as biomarkers and targets for therapeutic development.