bluuebunny/crossref_metadata_2025 huggingface dataset:
Determining the Psychometric Properties of Siddiqui Anxiety Scale-Revised
Authors: Salim Sabaenah , Siddiqui Salma
Published: July 2021

This study aimed to determine the psychometric properties of the Siddiqui Anxiety Scale (Hasnain & Siddiqui, 1993) in the Pakistani community. A pilot study with 15 males and 15 females (mean age = 25.07 years) was carried out to reassess its language and comprehensiveness, followed by a committee review by four mental health professionals. The validity and reliability estimates of Siddiqui Anxiety Scale-Revised (SAS-R) with 27 items were determined in the main study, using a convenient sample of university students (N=494) including 215 males and 279 females with a mean age of 20.8 years. Cronbach’s alpha reliability of SAS-R was found to be 0.90. The exploratory factor analysis revealed two factors in SAS-R (i.e., cognitive-affective and somatic), accounting for 34.48% cumulative variance. The convergent and divergent validity was determined by comparing it with Urdu translations of Beck Anxiety Inventory (BAI) (Raza, 2013) and Life Orientation Scale-Revised (LOT-R) (Shaheen, Tabassum, & Andleeb, 2015), respectively. SAS-R has a positive correlation with BAI and a significant negative correlation with LOT-R for optimism subscale and pessimism subscale. Furthermore, a cut-off score of 30 was determined using ROC curve analysis, obtaining a sensitivity index of 81.4 %, specificity index of 77.66%, the positive predictive power of 53.3%, and negative predictive power of 93% in the community sample. The psychometric properties of SAS-R are found to be robust enough to be recommended for screening anxiety symptoms in the Pakistani community.
The Review of Anti-aging Mechanism of Polyphenols on Caenorhabditis elegans
Authors: Liu Limin , Guo Peisen , Wang Peixi , Zheng Shanqing , Qu Zhi , Liu Nan
Published: July 2021

Micronutrients extracted from natural plants or made by biological synthesis are widely used in anti-aging research and applications. Among more than 30 effective anti-aging substances, employing polyphenol organic compounds for modification or delaying of the aging process attracts great interest because of their distinct contribution in the prevention of degenerative diseases, such as cardiovascular disease and cancer. There is a profound potential for polyphenol extracts in the research of aging and the related diseases of the elderly. Previous studies have mainly focused on the properties of polyphenols implicated in free radical scavenging; however, the anti-oxidant effect cannot fully elaborate its biological functions, such as neuroprotection, Aβ protein production, ion channel coupling, and signal transduction pathways. Caenorhabditis elegans (C. elegans) has been considered as an ideal model organism for exploring the mechanism of anti-aging research and is broadly utilized in screening for natural bioactive substances. In this review, we have described the molecular mechanisms and pathways responsible for the slowdown of aging processes exerted by polyphenols. We also have discussed the possible mechanisms for their anti-oxidant and anti-aging properties in C. elegans from the perspective of different classifications of the specific polyphenols, such as flavonols, anthocyanins, flavan-3-ols, hydroxybenzoic acid, hydroxycinnamic acid, and stilbenes.
Conditioned Medium of Bone Marrow Mesenchymal Stem Cells Involved in Acute Lung Injury by Regulating Epithelial Sodium Channels via miR-34c
Authors: Zhou Zhiyu , Hua Yu , Ding Yan , Hou Yapeng , Yu Tong , Cui Yong , Nie Hongguang
Published: July 2021

Background

One of the characteristics of acute lung injury (ALI) is severe pulmonary edema, which is closely related to alveolar fluid clearance (AFC). Mesenchymal stem cells (MSCs) secrete a wide range of cytokines, growth factors, and microRNA (miRNAs) through paracrine action to participate in the mechanism of pulmonary inflammatory response, which increase the clearance of edema fluid and promote the repair process of ALI. The epithelial sodium channel (ENaC) is the rate-limiting step in the sodium–water transport and edema clearance in the alveolar cavity; the role of bone marrow-derived MSC-conditioned medium (BMSC-CM) in edema clearance and how miRNAs affect ENaC are still seldom known.

Methods

CCK-8 cell proliferation assay was used to detect the effect of BMSC-CM on the survival of alveolar type 2 epithelial (AT2) cells. Real-time polymerase chain reaction (RT-PCR) and western blot were used to detect the expression of ENaC in AT2 cells. The effects of miR-34c on lung fluid absorption were observed in LPS-treated mice in vivo, and the transepithelial short-circuit currents in the monolayer of H441 cells were examined by the Ussing chamber setup. Dual luciferase reporter gene assay was used to detect the target gene of miR-34c.

Results

BMSC-CM could increase the viability of mouse AT2 cells. RT-PCR and western blot results showed that BMSC-CM significantly increased the expression of the γ-ENaC subunit in mouse AT2 cells. MiR-34c could restore the AFC and lung wet/dry weight ratio in the ALI animal model, and Ussing chamber assay revealed that miR-34c enhanced the amiloride-sensitive currents associated with ENaC activity in intact H441 cell monolayers. In addition, we observed a higher expression of miR-34c in mouse AT2 cells administrated with BMSC-CM, and the overexpression or inhibition of miR-34c could regulate the expression of ENaC protein and alter the function of ENaC. Finally, we detected that myristoylated alanine-rich C kinase substrate (MARCKS) may be one of the target genes of miR-34c.

Conclusion

Our results indicate that BMSC-CM may alleviate LPS-induced ALI through miR-34c targeting MARCKS and regulate ENaC indirectly, which further explores the benefit of paracrine effects of bone marrow-derived MSCs on edematous ALI.
Purification and Characterization of Nitphym, a Robust Thermostable Nitrilase From Paraburkholderia phymatum
Authors: Bessonnet Thomas , Mariage Aline , Petit Jean-Louis , Pellouin Virginie , Debard Adrien , Zaparucha Anne , Vergne-Vaxelaire Carine , de Berardinis Véronique
Published: July 2021

Despite the success of some nitrilases in industrial applications, there is a constant demand to broaden the catalog of these hydrolases, especially robust ones with high operational stability. By using the criteria of thermoresistance to screen a collection of candidate enzymes heterologously expressed in Escherichia coli, the enzyme Nitphym from the mesophilic organism Paraburkholderia phymatum was selected and further characterized. Its quick and efficient purification by heat treatment is of major interest for large-scale applications. The purified nitrilase displayed a high thermostability with 90% of remaining activity after 2 days at 30°C and a half-life of 18 h at 60°C, together with a broad pH range of 5.5–8.5. Its high resistance to various miscible cosolvents and tolerance to high substrate loadings enabled the quantitative conversion of 65.5 g⋅L–1 of 3-phenylpropionitrile into 3-phenylpropionic acid at 50°C in 8 h at low enzyme loadings of 0.5 g⋅L–1, with an isolated yield of 90%. This study highlights that thermophilic organisms are not the only source of industrially relevant thermostable enzymes and extends the scope of efficient nitrilases for the hydrolysis of a wide range of nitriles, especially trans-cinnamonitrile, terephthalonitrile, cyanopyridines, and 3-phenylpropionitrile.
Robust Angiogenesis and Arteriogenesis in the Skin of Diabetic Mice by Transient Delivery of Engineered VEGF and PDGF-BB Proteins in Fibrin Hydrogels
Authors: Certelli Alessandro , Valente Paolo , Uccelli Andrea , Grosso Andrea , Di Maggio Nunzia , D’Amico Rosalinda , Briquez Priscilla S. , Hubbell Jeffrey A. , Wolff Thomas , Gürke Lorenz , Mujagic Edin , Gianni-Barrera Roberto , Banfi Andrea
Published: July 2021

Non-healing ulcers are a serious complication of diabetes mellitus and a major unmet medical need. A major cause for the lack of healing is the impairment of spontaneous vascularization in the skin, despite mostly normal blood flow in deeper large vessels. Therefore, pro-angiogenic treatments are needed to increase therapeutic perfusion by recruiting new arterial connections (therapeutic arteriogenesis). Vascular endothelial growth factor (VEGF) is the master regulator of angiogenesis in physiology and disease, but exploitation of its therapeutic potential requires careful control of its dose distribution in tissue. Co-delivery of platelet derived growth factor-BB (PDGF-BB) has been shown to expand the therapeutic window of VEGF and also improve associated arteriogenesis. We used a highly controlled protein delivery system, based on a clinically applicable fibrin-based platform, to investigate the angiogenic and arteriogenic potential of engineered versions (TG-) of VEGF and PDGF-BB proteins in the skin of diabetic and obese db/db mice. Intradermal delivery of therapeutically relevant doses of TG-VEGF and TG-PDGF-BB induced robust growth of new microvascular networks with similar efficacy as in normal littermate control mice. Further, TG-PDGF-BB prevented the formation of aberrant vascular enlargements by high TG-VEGF levels. As fibrin was degraded after the first week, the induced angiogenesis mostly regressed by 4 weeks, but it promoted effective arteriogenesis in the dermal layer. Therefore, controlled co-delivery of TG-VEGF and TG-PDGF-BB recombinant proteins is effective to induce angiogenesis and arteriogenesis in diabetic mouse skin and should be further investigated to promote diabetic wound healing.
Structural and Functional Characterization of a Testicular Long Non-coding RNA (4930463O16Rik) Identified in the Meiotic Arrest of the Mouse Topaz1–/– Testes
Authors: Chadourne Manon , Poumerol Elodie , Jouneau Luc , Passet Bruno , Castille Johan , Sellem Eli , Pailhoux Eric , Mandon-Pépin Béatrice
Published: July 2021

Spermatogenesis involves coordinated processes, including meiosis, to produce functional gametes. We previously reportedTopaz1as a germ cell-specific gene highly conserved in vertebrates.Topaz1knockout males are sterile with testes that lack haploid germ cells because of meiotic arrest after prophase I. To better characterizeTopaz1–/–testes, we used RNA-sequencing analyses at two different developmental stages (P16 and P18). The absence of TOPAZ1 disturbed the expression of genes involved in microtubule and/or cilium mobility, biological processes required for spermatogenesis. Moreover, a quarter of P18 dysregulated genes are long non-coding RNAs (lncRNAs), and three of them are testis-specific and located in spermatocytes, their expression starting between P11 and P15. The suppression of one of them,4939463O16Rik, did not alter fertility although sperm parameters were disturbed and sperm concentration fell. The transcriptome of P18-4939463O16Rik–/–testes was altered and the molecular pathways affected included microtubule-based processes, the regulation of cilium movement and spermatogenesis. The absence of TOPAZ1 protein or4930463O16Rikproduced the same enrichment clusters in mutant testes despite a contrasted phenotype on male fertility. In conclusion, althoughTopaz1is essential for the meiosis in male germ cells and regulate the expression of numerous lncRNAs, these studies have identified aTopaz1regulated lncRNA (4930463O16Rik) that is key for both sperm production and motility.
Increased PD-1 Level in Severe Cervical Injury Is Associated With the Rare Programmed Cell Death 1 (PDCD1) rs36084323 A Allele in a Dominant Model
Authors: Silva Mauro César da , Medeiros Fernanda Silva , Silva Neila Caroline Henrique da , Paiva Larissa Albuquerque , Gomes Fabiana Oliveira dos Santos , Costa e Silva Matheus , Gomes Thailany Thays , Peixoto Christina Alves , Rygaard Maria Carolina Valença , Menezes Maria Luiza Bezerra , Welkovic Stefan , Donadi Eduardo Antônio , Lucena-Silva Norma
Published: July 2021

The high-risk oncogenic human papillomavirus (HPV) has developed mechanisms for evasion of the immune system, favoring the persistence of the infection. The chronic inflammation further contributes to the progression of tissue injury to cervical cancer. The programmed cell death protein (PD-1) after contacting with its ligands (PD-L1 and PD-L2) exerts an inhibitory effect on the cellular immune response, maintaining the balance between activation, tolerance, and immune cell-dependent lesion. We evaluated 295 patients exhibiting or not HPV infection, stratified according to the location (injured and adjacent non-injured areas) and severity of the lesion (benign, pre-malignant lesions). Additionally, we investigated the role of the promoter region PDCD1 -606G>A polymorphism (rs36084323) on the studied variables. PD-1 and PDCD1 expression were evaluated by immunohistochemistry and qPCR, respectively, and the PDCD1 polymorphism was evaluated by nucleotide sequencing. Irrespective of the severity of the lesion, PD-1 levels were increased compared to adjacent uninjured areas. Additionally, in cervical intraepithelial neoplasia (CIN) I, the presence of HPV was associated with increased (P = 0.0649), whereas in CIN III was associated with decreased (P = 0.0148) PD-1 levels, compared to the uninjured area in absence of HPV infection. The PDCD1 -606A allele was rare in our population (8.7%) and was not associated with the risk for development of HPV infection, cytological and histological features, and aneuploidy. In contrast, irrespective of the severity of the lesion, patients exhibiting the mutant PDCD1 -606A allele at single or double doses exhibited increased protein and gene expression when compared to the PDCD1 -606GG wild type genotype. Besides, the presence of HPV was associated with the decrease in PDCD1 expression and PD-1 levels in carriers of the -606 A allele presenting severe lesions, suggesting that other mediators induced during the HPV infection progression may play an additional role. This study showed that increased PD-1 levels are influenced by the -606G>A nucleotide variation, particularly in low-grade lesions, in which the A allele favors increased PDCD1 expression, contributing to HPV immune system evasion, and in the high-grade lesion, by decreasing tissue PD-1 levels.
Comparison of Cryptococcus gattii/neoformans Species Complex to Related Genera (Papiliotrema and Naganishia) Reveal Variances in Virulence Associated Factors and Antifungal Susceptibility
Authors: Oliveira Lana Sarita de Souza , Pinto Luciana Magalhães , de Medeiros Mariana Araújo Paulo , Toffaletti Dena L. , Tenor Jennifer L. , Barros Tânia Fraga , Neves Rejane Pereira , Neto Reginaldo Gonçalves de Lima , Milan Eveline Pipolo , Padovan Ana Carolina Barbosa , Rocha Walicyranison Plinio da Silva , Perfect John R. , Chaves Guilherme Maranhão
Published: July 2021

Cryptococcosis is an infectious disease of worldwide distribution, caused by encapsulated yeasts belonging to the phylum Basidiomycota. The genus Cryptococcus includes several species distributed around the world. The C. gattii/neoformans species complex is largely responsible for most cases of cryptococcosis. However, clinical series have been published of infections caused by Papiliotrema (Cryptococcus) laurentii and Naganishia albida (Cryptococcus albidus), among other related genera. Here, we examined the pathogenic potential and antifungal susceptibility of C. gattii/neoformans species complex (clades I and II) and related genera (Papiliotrema and Naganishia) isolated from environmental and clinical samples. P. laurentii (clade III), N. liquefasciens/N. albidosimilis (clade IV); and N. adeliensis/N. albida (clade V) strains produced higher levels of phospholipase and hemolysins, whereas the C. gattii/neoformans species complex strains (clades I and II) had markedly thicker capsules, produced more biofilm biomass and melanin, which are known virulence attributes. Interestingly, 40% of C. neoformans strains (clade II) had MICs above the ECV established for this species to amphotericin B. Several non-C. gattii/neoformans species complex (clades III to V) had MICs equal to or above the ECVs established for C. deuterogattii and C. neoformans for all the three antifungal drugs tested. Finally, all the non-C. gattii/neoformans clinical isolates (clades III to V) produced more melanin than the environmental isolates might reflect their particularly enhanced need for melanin during in vivo protection. It is very clear that C. gattii/neoformans species complex (clades I and II) strains, in general, show more similar virulence phenotypes between each other when compared to non-C. gattii/neoformans species complex (clades III to V) isolates. These observations together with the fact that P. laurentii and Naganishia spp. (clades III to V) strains were collected from the outside of a University Hospital, identify features of these yeasts important for environmental and patient colonization and furthermore, define mechanisms for infections with these uncommon pathogens.
Case Report: A Novel NKX2-5 Mutation in a Family With Congenital Heart Defects, Left Ventricular Non-compaction, Conduction Disease, and Sudden Cardiac Death
Authors: Morlanes-Gracia Paula , Antoniutti Guido , Alvarez-Rubio Jorge , Torres-Juan Laura , Heine-Suñer Damian , Ripoll-Vera Tomás
Published: July 2021

The NKX2-5 gene encodes for a transcription factor crucial for cardiac cell differentiation and proliferation. It was the first gene associated with congenital heart disease (CHD) in humans and has been linked to conduction disorders or cardiomyopathies. However, an overlapping phenotype is not frequent in the literature. We describe a family with a novel missense mutation in the NKX2-5 gene (p.Gln181Pro) with numerous antecedents with atrial septal defect (ASD), left ventricular non-compaction (LVNC), conduction disease, and sudden cardiac death (SCD).
Seismic Reflection Images of Possible Mantle-Fluid Conduits and Basal Erosion in the 2011 Tohoku Earthquake Rupture Area
Authors: Park Jin-Oh , Tsuru Tetsuro , Fujie Gou , Jamali Hondori Ehsan , Kagoshima Takanori , Takahata Naoto , Zhao Dapeng , Sano Yuji
Published: July 2021

Multi-channel seismic reflection and sub-bottom profiling data reveal landward-dipping normal faults as potential conduits for mantle-derived fluids in the coseismic slip area of the 2011 Tohoku earthquake (Mw9.0). Normal faults below the helium isotope anomaly sites appear to develop through the forearc crust (i.e., the seafloor sedimentary section and Cretaceous basement) and to evolve to lower dip angles as extension progresses deeper, potentially extending down to the mantle wedge, despite their intermittently continuous reflections. The faults are characterized by high-amplitude, reverse-polarity reflections within the Cretaceous basement. Moreover, deep extension of the faults connecting to a low-velocity region spreading from the Cretaceous basement into the mantle wedge across the forearc Moho suggests that the faults are overpressured by local filling with mantle-derived fluids. The locations of the normal faults are roughly consistent with aftershocks of the 2011 Tohoku earthquake, which show normal-faulting focal mechanisms. The 2011 Tohoku mainshock and subsequent aftershocks can lead the pre-existing normal faults to be reactive and more permeable so that locally trapped mantle fluids can migrate up to the seafloor through fault fracture zones. The reactivated normal faults may be an indicator of shallow coseismic slip to the trench. Locally elevated fluid pressures can decrease the effective normal stress for the fault plane, facilitating easier slip along the fault and local tsunami. The landward-dipping normal faults developing from the seafloor down into the Cretaceous basement are predominant in the middle slope region of the forearc. A possible shear zone with high-amplitude, reverse-polarity reflections above the plate interface, which is almost localized to the middle slope region, suggests more intense basal erosion of the overlying plate in that region.
Cultural Validity as Foundational to Assessment Development: An Indigenous Example
Authors: Kūkea Shultz Pōhai , Englert Kerry
Published: July 2021

The state of Hawai‘i has a linguistically and culturally diverse population that recognizes Hawaiian and English as official languages. Working with the community, the state established the Hawaiian Language Immersion Program, Ka Papahana Kaiapuni Hawai‘i (Kaiapuni), to support and promote the study of Hawaiian language, culture, and history. Kaiapuni students are historically marginalized test-takers and had been assessed using instruments that were culturally and linguistically insensitive, contained construct irrelevant variance, or had inadequate psychometric properties (U. S. Department of Education, 2006;Kaawaloa, 2014). In response, the Hawai‘i State Department of Education and the University of Hawai‘i developed the Kaiapuni Assessment of Educational Outcomes (KĀʻEO), which engages Kaiapuni students in technically rigorous, Native language assessments. This article details the theoretical framework of the KĀʻEO program, which includes traditional validity studies to build content and construct validity that support the assessment’s use for accountability. However, the KĀʻEO team recognized that additional evidence was needed because the KĀʻEO theory of action is grounded in principles of community use of assessment scores to advance cultural and language revitalization. The article provides an example of one of the validity studies that the team conducted to build evidence in support of cultural and content validity.
Case Report: Three Rare Cases of Ectopic ACTH Syndrome Caused by Adrenal Medullary Hyperplasia
Authors: Cheng Yu , Li Jie , Dou Jingtao , Ba Jianming , Du Jin , Zhang Saichun , Mu Yiming , Lv Zhaohui , Gu Weijun
Published: July 2021

Ectopic ACTH syndrome (EAS) accounts for 10–20% of endogenous Cushing’s syndrome (CS). Hardly any cases of adrenal medullary hyperplasia have been reported to ectopically secrete adrenocorticotropic hormone (ACTH). Here we describe a series of three patients with hypercortisolism secondary to ectopic production of ACTH from adrenal medulla. Cushingoid features were absent in case 1 but evident in the other two cases. Marked hypokalemia was found in all three patients, but hyperglycemia and osteoporosis were present only in case 2. All three patients showed significantly elevated serum cortisol and 24-h urinary cortisol levels. The ACTH levels ranged from 19.8 to 103.0pmol/L, favoring ACTH-dependent Cushing’s syndrome. Results of bilateral inferior petrosal sinus sampling (BIPSS) for case 1 and case 3 confirmed ectopic origin of ACTH. The extremely high level of ACTH and failure to suppress cortisol with high dose dexamethasone suppression test (HDDST) suggested EAS for patient 2. However, image studies failed to identify the source of ACTH secretion. Bilateral adrenalectomy was performed for rapid control of hypercortisolism. After surgery, cushingoid features gradually disappeared for case 2 and case 3. Blood pressure, blood glucose and potassium levels returned to normal ranges without medication for case 2. The level of serum potassium also normalized without any supplementation for case 1 and case 3. The ACTH levels of all three patients significantly decreased 3-6 months after surgery. Histopathology revealed bilateral adrenal medullary hyperplasia and immunostaining showed positive ACTH staining located in adrenal medulla cells. In summary, our case series reveals the adrenal medulla to be a site of ectopic ACTH secretion. Adrenal medulla-originated EAS makes the differential diagnosis of ACTH-dependent Cushing’s syndrome much more difficult. Control of the hypercortisolism is mandatory for such patients.
BTK Inhibitors in Chronic Lymphocytic Leukemia: Biological Activity and Immune Effects
Authors: Palma Marzia , Mulder Tom A. , Österborg Anders
Published: July 2021

Bruton´s tyrosine kinase (BTK) inhibitor (BTKi)s block the B-cell receptor (BCR) signaling cascade by binding to the BTK enzyme preventing the proliferation and survival of malignant and normal B cells. During the past decade, the clinical use of BTKis for the treatment of B-cell malignancies has exponentially grown, changing the treatment landscape for chronic lymphocytic leukemia (CLL) in particular. At present, three different covalent BTKis, ibrutinib, acalabrutinib and zanubrutinib, are FDA-approved and many new inhibitors are under development. Despite having remarkable selectivity for BTK, the first-in-class BTKi ibrutinib can also bind, with various affinities, to other kinases. The combined inhibition of BTK (“on-target” effect) and other kinases (“off-target” effect) can have additive or synergistic anti-tumor effects but also induce undesired side effects which might be treatment-limiting. Such “off-target” effects are expected to be more limited for second-generation BTKis. Moreover, the blockade of BCR signaling also indirectly affects the tumor microenvironment in CLL. Treatment with BTKis potentially impacts on both innate and adaptive immunity. Whether this affects infection susceptibility and vaccination efficacy requires further investigation. Here, we summarize the available knowledge on the impact of BTKis on the immune system and discuss the possible clinical implications. Indeed, a deeper knowledge on this topic could guide clinicians in the management and prevention of infections in patients with CLL treated with BTKis.
Diagnosis of Mycobacterium tuberculosis Septic Shock in Patients With Anti-synthetase Syndrome Based on Next-Generation Sequencing: A Case Report and Literature Review
Authors: Sun Limin , Yang Ziyue , Yang Fei , Wang Zhenhua , Li Hongqiang , Wang Huifen , Sun Tongwen
Published: July 2021

A 51-year-old woman was transferred to the intensive care unit with such symptoms as fever, swollen left knee joint, pain and hypotension. After preliminary evaluation, she was diagnosed as suffering acute suppurative arthritis and septic shock. Then, she was rescued and prescribed to receive treatment with broad-spectrum antibiotics. However, there was no source of infection identified except for the knee joint. The bacterial and fungal cultures of blood samples and articular effusion were shown to be negative, while the results obtained from the next-generation sequencing of blood and articular effusion revealed that Mycobacterium tuberculosis was positive. The patient was then put on five combinations of anti-tuberculosis therapeutic treatment. Nevertheless, despite the active anti-tuberculosis treatment put in place, her general condition still deteriorated progressively. As the level of her bilirubin continued to rise, further treatment was affected, which prompted the change made to the anti-tuberculosis treatment program. Her clinical condition continued to deteriorate, which led to the development of unstable vital signs and the multiple organ dysfunction syndrome. In spite of our best efforts to save her life, the patient still ended up with death.
Characterization of the Exometabolome of Nitrosopumilus maritimus SCM1 by Liquid Chromatography–Ion Mobility Mass Spectrometry
Authors: Law Kai P. , He Wei , Tao Jianchang , Zhang Chuanlun
Published: July 2021

Marine Thaumarchaeota (formerly known as the marine group I archaea) have received much research interest in recent years since these chemolithoautotrophic organisms are abundant in the subsurface ocean and oxidize ammonium to nitrite, which makes them a major contributor to the marine carbon and nitrogen cycles. However, few studies have investigated the chemical composition of their exometabolome and their contributions to the pool of dissolved organic matter (DOM) in seawater. This study exploits the recent advances in ion mobility mass spectrometry (IM-MS) and integrates this instrumental capability with bioinformatics to reassess the exometabolome of a model ammonia-oxidizing archaeon, Nitrosopumilus maritimus strain SCM1. Our method has several advantages over the conventional approach using an Orbitrap or ion cyclotron resonance mass analyzer and allows assignments or annotations of spectral features to known metabolites confidently and indiscriminately, as well as distinction of biological molecules from background organics. Consistent with the results of a previous report, the SPE-extracted exometabolome of N. maritimus is dominated by biologically active nitrogen-containing metabolites, in addition to peptides secreted extracellularly. Cobalamin and associated intermediates, including α-ribazole and α-ribazole 5′-phosphate, are major components of the SPE-extracted exometabolome of N. maritimus. This supports the proposition that Thaumarchaeota have the capacity of de novo biosynthesizing cobalamin. Other biologically significant metabolites, such as agmatidine and medicagenate, predicted by genome screening are also detected, which indicates that Thaumarchaeota have remarkable metabolic potentials, underlining their importance in driving elemental cycles critical to biological processes in the ocean.
The Proposed Molecular Mechanisms Used by Archaea for Fe(III) Reduction and Fe(II) Oxidation
Authors: Dong Yiran , Shan Yawei , Xia Kemin , Shi Liang
Published: July 2021

Iron (Fe) is the fourth most abundant element in the Earth’s crust where ferrous Fe [Fe(II)] and ferric Fe [Fe(III)] can be used by archaea for energy conservation. In these archaea-Fe interactions, Fe(III) serves as terminal electron acceptor for anaerobic respiration by a variety of archaea, while Fe(II) serves as electron donor and/or energy sources for archaeal growth. As no Fe is incorporated into the archaeal cells, these redox reactions are referred to as dissimilatory Fe(III) reduction and Fe(II) oxidation, respectively. Dissimilatory Fe(III)-reducing archaea (FeRA) and Fe(II)-oxidizing archaea (FeOA) are widespread on Earth where they play crucial roles in biogeochemical cycling of not only Fe, but also carbon and sulfur. To reduce extracellular Fe(III) (oxyhydr)oxides, some FeRA transfer electrons directly to the Fe(III) (oxyhydr)oxides most likely via multiheme c-type cytochromes (c-Cyts). These multiheme c-Cyts may form the pathways similar to those found in bacteria for transferring electrons from the quinone/quinol pool in the cytoplasmic membrane to the Fe(III) (oxyhydr)oxides external to the archaeal cells. Use of multiheme c-Cyts for extracellular Fe(III) reduction by both Domains of Archaea and Bacteria emphasizes an ancient mechanism of extracellular electron transfer, which is well conserved. Other FeRA, however, reduce Fe(III) (oxyhydr)oxides indirectly via electron shuttles. Similarly, it is proposed that FeOA use pathways to oxidize Fe(II) on the surface of the cytoplasmic membrane and then to transfer the released electrons across the cytoplasmic membrane inward to the O2 and NAD+ in the cytoplasm. In this review, we focus on the latest understandings of the molecular mechanisms used by FeRA and FeOA for Fe(III) reduction and Fe(II) oxidation, respectively.
Oxygen-Based Nanocarriers to Modulate Tumor Hypoxia for Ameliorated Anti-Tumor Therapy: Fabrications, Properties, and Future Directions
Authors: Li Xianqiang , Wu Yue , Zhang Rui , Bai Wei , Ye Tiantian , Wang Shujun
Published: July 2021

Over the past five years, oxygen-based nanocarriers (NCs) to boost anti-tumor therapy attracted tremendous attention from basic research and clinical practice. Indeed, tumor hypoxia, caused by elevated proliferative activity and dysfunctional vasculature, is directly responsible for the less effectiveness or ineffective of many conventional therapeutic modalities. Undeniably, oxygen-generating NCs and oxygen-carrying NCs can increase oxygen concentration in the hypoxic area of tumors and have also been shown to have the ability to decrease the expression of drug efflux pumps (e.g., P-gp); to increase uptake by tumor cells; to facilitate the generation of cytotoxic reactive oxide species (ROS); and to evoke systematic anti-tumor immune responses. However, there are still many challenges and limitations that need to be further improved. In this review, we first discussed the mechanisms of tumor hypoxia and how it severely restricts the therapeutic efficacy of clinical treatments. Then an up-to-date account of recent progress in the fabrications of oxygen-generating NCs and oxygen-carrying NCs are systematically introduced. The improved physicochemical and surface properties of hypoxia alleviating NCs for increasing the targeting ability to hypoxic cells are also elaborated with special attention to the latest nano-technologies. Finally, the future directions of these NCs, especially towards clinical translation, are proposed. Therefore, we expect to provide some valued enlightenments and proposals in engineering more effective oxygen-based NCs in this promising field in this comprehensive overview.
Acupuncture-Related Therapies for Parkinson's Disease: A Meta-Analysis and Qualitative Review
Authors: Wen Xiaopeng , Li Kunbin , Wen Hao , Wang Qian , Wu Zhiyuan , Yao Xianli , Jiao Bing , Sun Pingge , Ge Shuqi , Wen Chenyang , Lu Liming
Published: July 2021

Objective: This systematic review and meta-analysis aimed to assess the effects of the combination of acupuncture-related therapies with conventional medication compared with conventional medication in patients with Parkinson's disease (PD).

Methods: A literature search within eight databases [including Medline, Embase, the Cochrane Library, PubMed, China National Knowledge Infrastructure (CNKI), China Biology Medicine (CBM), VIP, and Wanfang Database] was performed covering a time frame from their inception to August 2020. Randomized controlled trials (RCTs) comparing acupuncture-related therapies combined with conventional medication vs. conventional medication in patients with PD were eligible. Two authors independently assessed the risk of bias. Assessments were performed with the total and subscales scores of the Unified Parkinson's Disease Rating Scale (UPDRS), 39-item Parkinson's Disease Questionnaire (PDQ-39), the dosage of Madopar, Mini-Mental State Examination (MMSE), and 17-item Hamilton Depression Scale (HAMD). Data were analyzed by adopting the Cochrane Collaboration's RevMan 5.4 (Review Man, Copenhagen, Denmark); and mean effect sizes and 95% confidence intervals were estimated. Tests for heterogeneity were used to assess differences in treatment effects across different types of acupuncture used.

Results: Sixty-six trials met the inclusion criteria, of which 61 trials provided data for the meta-analysis. We defined high-quality articles as those with a low risk of bias in four or more domains; and only 10 (15.15%) articles were of high quality. Compared with the controls, acupuncture-related therapies with conventional medication achieved a benefit in the primary outcomes of UPDRS (motor subscore: −3.90, −4.33 to −3.49, P < 0.01; total score: −7.37 points, −8.91 to −5.82, P < 0.001; activities of daily living subscore: −3.96, −4.96 to −2.95, P < 0.01). For the subgroup difference test among the effects of different acupuncture methods, significant differences existed in outcomes with the UPDRS-III, UPDRS-I, UPDRS-IV, and PDQ-39 scores and Madopar dosage, while non-significant differences existed with the UPDRS-total, UPDRS-II, HAMD, and MMSE scores.

Conclusions: Acupuncture-related therapies combined with conventional medication may benefit individuals with PD. Our review findings should be considered with caution because of the methodological weaknesses in the included trials. Future, large randomized trials of acupuncture-related therapies for PD with high methodological quality are warranted.

Systematic Review Registration: Identifier CRD42021228110.
Distinctive Association of the Functional Connectivity of the Posterior Cingulate Cortex on Memory Performances in Early and Late Amnestic Mild Cognitive Impairment Patients
Authors: Kang Dong Woo , Wang Sheng-Min , Um Yoo Hyun , Na Hae-Ran , Kim Nak-Young , Lee Chang Uk , Lim Hyun Kook
Published: July 2021

Background

Attempts have been made to explore the biological basis of neurodegeneration in the amnestic mild cognitive impairment (MCI) stage, subdivided by memory performance. However, few studies have evaluated the differential impact of functional connectivity (FC) on memory performances in early- and late-MCI patients.

Objective

This study aims to explore the difference in FC of the posterior cingulate cortex (PCC) among healthy controls (HC) (n= 37), early-MCI patients (n= 30), and late-MCI patients (n= 35) and to evaluate a group-memory performance interaction against the FC of PCC.

Methods

The subjects underwent resting-state functional MRI scanning and a battery of neuropsychological tests.

Results

A significant difference among the three groups was found in FC between the PCC (seed region) and bilateral crus cerebellum, right superior medial frontal gyrus, superior temporal gyrus, and left middle cingulate gyrus (Monte Carlo simulation-correctedp< 0.01; clusterp< 0.05). Additionally, the early-MCI patients displayed higher FC values than the HC and late-MCI patients in the right superior medial frontal gyrus, cerebellum crus 1, and left cerebellum crus 2 (Bonferroni-correctedp< 0.05). Furthermore, there was a significant group-memory performance interaction (HCvs. early MCIvs. late MCI) for the FC between PCC and bilateral crus cerebellum, right superior medial frontal gyrus, superior temporal gyrus, and left middle cingulate gyrus (Bonferroni-correctedp< 0.05).

Conclusion

These findings contribute to the biological implications of early- and late-MCI stages, categorized by evaluating the impairment of memory performance. Additionally, comprehensively analyzing the structural differences in the subdivided amnestic MCI (aMCI) stages could deepen our understanding of these biological meanings.
BK Channel-Mediated Microglial Phagocytosis Alleviates Neurological Deficit After Ischemic Stroke
Authors: Huang Shuxian , Chen Tingting , Suo Qian , Shi Rubing , Khan Haroon , Ma Yuanyuan , Tang Yaohui , Yang Guo-Yuan , Zhang Zhijun
Published: July 2021

Microglial phagocytosis benefits neurological recovery after stroke. Large-conductance Ca2+-activated K+ currents are expressed in activated microglia, and BK channel knockout aggravates cerebral ischemic injury. However, the effect of BK channels on microglial phagocytosis after ischemic stroke remains unknown. Here, we explored whether BK channel activation is beneficial for neurological outcomes through microglial phagocytosis after ischemic stroke. ICR mice after transient middle cerebral artery occlusion (tMCAO) were treated with dimethyl sulfoxide (DMSO), BK channel activator NS19504, and inhibitor Paxilline. The results showed a decrease in BK channel expression after tMCAO. BK channel activator NS19504 alleviates neurological deficit after experimental modeling of tMCAO in mice compared to the control. Furthermore, we treated primary microglia with DMSO, NS19504, and Paxilline after oxygen glucose deprivation (OGD). NS19504 promoted primary microglial phagocytosing fluorescent beads and neuronal debris, which reduced neuronal apoptosis after stroke. These effects could be reversed by BK channel inhibitor Paxilline. Finally, NS19504 increased relative phosphorylated extracellular signal-regulated kinase 1/2 expression compared to the Paxilline group at the third day after stroke. Our findings indicate that microglial BK channels are a potential target for acute stage of ischemic stroke therapy.
Clinical Determinants of Disease Progression in Patients With Beta-Sarcoglycan Gene Mutations
Authors: Marchetti Giulia Bruna , Valenti Luca , Torrente Yvan
Published: July 2021

Background: Limb-girdle muscular dystrophy 2E (LGMD 2E), recently renamed as autosomal recessive limb-girdle muscular dystrophy-4 (LGMDR4), is characterized by the lack of beta-sarcoglycan, normally expressed in skeletal muscles and cardiomyocytes. We hypothesized that progressive respiratory and left ventricular (LV) failure in LGMDR4 could be associated with the age and interrelated phenomena of the disease's natural history.

Methods: We conducted a retrospective review of the records of 26 patients with LGMDR4. Our primary objective was to compare the rates of decline among creatine phosphokinase (CPK) values, pulmonary function test (PFT) measures, and echocardiographic estimates and to relate them to patients' age.

Results: The rates of decline/year of CPK, PFTs, and LV function estimates are significatively bound to age, with the LV ejection fraction (EF) being the strongest independent variable describing disease progression. Moreover, the rate of decline of CPK, PFTs, and LV differed in patients grouped according to their genetic mutations, demonstrating a possible genotype–phenotype correlation. The parallel trend of decline in CPK, PFT, and EF values demonstrates the presence in LGMDR4 of a simultaneous and progressive deterioration in muscular, respiratory, and cardiac function.

Conclusions: This study expands the current knowledge regarding the trend of CPK values and cardiac and respiratory impairment in patients with LGMDR4, to optimize the monitoring of these patients, to improve their quality of life, and to provide clinical indices capable of quantifying the effects of any new gene or drug therapy.
Does Intensive Training of Attention Influence Cognitive Fatigability in Patients With Acquired Brain Injury?
Authors: Holmqvist Anna , Bartfai Aniko , Markovic Gabriela , Möller Marika C.
Published: July 2021

Research Objectives

Impairments in attention and the speed of information processing are central to the experience of cognitive fatigue in patients with acquired brain injury (ABI). Attention may be improved through intensive training in a rehabilitation setting. The aim of the study was to investigate the feasibility of reducing cognitive fatigability (CF) using attention training and to explore the effect of two different approaches to attention training.

Design

Randomised controlled study in a rehabilitation setting.

Participants

59 patients (age 19–59 years) with mild to moderate stroke or traumatic brain injury in the early (<4 month) phase.

Interventions

Patients were randomly assigned to intensive specific training with Attention Process Training (APT) or Activity-Based Attention Training (ABAT) for 3–5 days per week for a period of 5–6 weeks with a total of 20 h, in addition to traditional interdisciplinary rehabilitation.

Main Outcome Measure

CF was conceptualised as performance decline in terms of an increased number of incorrect responses between the first and the last quintiles of the Paced Auditory Serial Addition Test (PASAT). A negative result was defined as fatigability. The evaluator of fatigability was blinded to treatment.

Results

At baseline, there were no differences between the groups in age, education, reasoning, anxiety or depression. After training, a significant treatment effect was found (p= 0.020), as the APT-group, but not the ABAT-group, had improved. However, after controlling for baseline differences regarding CF on the PASAT-f, the difference was no longer significant.

Conclusion

The results indicate that cognitive training might be a feasible method for reducing CF through attention training and that patients with high levels of CF benefit most from attention training. The type of intervention provided, whether specific or activity-based attention training, appears to be of less importance, as there was no treatment effect after controlling for the baseline level of CF. Future studies are required to confirm the validity of the findings.
Overcoming Resistance to Immunotherapy in Head and Neck Cancer Using Radiation: A Review
Authors: Hui Caressa , Chau Brittney , Gan Greg , Stokes William , Karam Sana D. , Amini Arya
Published: July 2021

Radiation therapy remains at the center of head and neck cancer treatment. With improvements in treatment delivery, radiation therapy has become an affective ablative modality for head and neck cancers. Immune checkpoint inhibitors are now also playing a more active role both in the locally advanced and metastatic setting. With improved systemic options, local noninvasive modalities including radiation therapy are playing a critical role in overcoming resistance in head and neck cancer. The aim of this review is to describe the role of radiation therapy in modulating the tumor microenvironment and how radiation dose, fractionation and treatment field can impact the immune system and potentially effect outcomes when combined with immunotherapy. The review will encompass several common scenarios where radiation is used to improve outcomes and overcome potential resistance that may develop with immunotherapy in head and neck squamous cell carcinoma (HNSCC), including upfront locally advanced disease receiving definitive radiation and recurrent disease undergoing re-irradiation. Lastly, we will review the potential toxicities of combined therapy and future directions of their role in the management of HNSCC.
Association of Biomarker Discrepancy and Treatment Decision, Disease Outcome in Recurrent/Metastatic Breast Cancer Patients
Authors: Lu Yujie , Tong Yiwei , Chen Xiaosong , Shen Kunwei
Published: July 2021

Background

Biomarker discrepancy between primary and recurrent/metastatic breast cancer is well known, however its impact on prognosis and treatment after relapse is still unclear. Current study aims to evaluate biomarkers discrepancy between primary and recurrent/metastatic lesions as well as to investigate its association with following treatment pattern and disease outcome.

Patients and methods

We retrospectively included consecutive breast cancer patients undergoing surgery in our center from Jan. 2009 to Dec. 2016 and reported disease recurrence. Patients with re-biopsy and paired biomarkers statuses on primary and recurrent/metastatic lesions were further analyzed. Kappa test was used to analyze the concordance rate of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor-2 (HER2) status. Post-recurrence survival (PRS) was compared between subgroups by Kaplan-Meier curve. Cox regression model was applied to identify impact factors for PRS.

Results

A total of 156 patients were finally included, of whom 70 and 86 had loco-regional and distant recurrence, respectively. Concordance rates of ER, PR and HER2 were 83.3%, 66.7%, and 97.1%, respectively, which was similarly distributed among different recurrent sites (all P > 0.05). Primary ER-positivity (vs ER-negativity, P = 0.014) and loco-regional recurrence (vs distant metastasis, P = 0.001) were independently associated with superior PRS, while patients with visceral metastasis (P < 0.001) had the worst disease outcome. Hormone receptor/HER2 status discrepancy was observed in 28 patients. Fifteen of them changed systemic treatment based on biomarker statuses of recurrent lesion, however, their PRS was not improved compared to those 13 patients who continued the same treatment according to primary biomarkers statuses (P = 0.298).

Conclusion

Biomarker discrepancy was observed between primary and recurrent/metastatic breast cancer lesions and had certain influence on treatment strategies after relapse. However, its impact on disease outcome wasn’t established in the current study, which deserves further evaluation.