bluuebunny/crossref_metadata_2025 huggingface dataset:
Life-Threatening Sinonasal Invasive Aspergillosis Easily Misdiagnosed
Authors: You Yeon Seok , Koh Ji Hoon , Kim Byeong Jin , Lee Eun Jung , Kwon Sam Hyun , Kim Jong Seung
Published: September 2022

Background and Objectives Invasive fungal sinusitis is extremely rare. Yet the consequences of this infection may be fatal if not diagnosed correctly at an early stage. We discuss three cases of Aspergillosis sphenoid sinusitis that were misdiagnosed and have led to fatal consequences.Subjects and Method This is a retrospective analysis of cases diagnosed as invasive fungal sinusitis of sphenoid sinus.Results All three cases were of men who had immunocompromised medical histories that included leukemia and diabetes mellitus. The patients presented symptoms that included fever, chronic headache, weakness on one side, and facial edema. In the first case, CT showed no suspicious lesions that indicated fungal infection. However, five days after being prescribed antibiotics, the patient suffered obstruction of the right internal carotid artery (ICA) and right cavernous sinus. In the second case, CT showed total obstruction in the left ICA and a soft tissue mass in the left sphenoid sinus that extended and involved the left cavernous sinus. In the last case, CT showed soft density progression in the right sphenoid sinus with bone erosion when compared to images taken eight days earlier. In each of these cases, we performed emergency endoscopic sinus surgery. One case was confirmed to be invasive aspergillosis by histology whereas the other two cases were suspected to be invasive aspergillosis based on their past medical histories, clinical findings and image studies.Conclusion Clinicians must take great care to rule out invasive aspergillosis in immunocompromised patients with sinusitis.
A Preliminary Analysis of the Costs and Benefits of Physical Therapy and Strength Training for Fighter Pilots
Authors: Erneston Christian G. , Fass R. David , Ritschel Jonathan D. , Cox Amy M.
Published: September 2022

BACKGROUND: Occupational hazards facing high performance aircraft pilots (“fighter” pilots) can cause injury, time lost from flying, and voluntary or involuntary career termination. The high cost of training and retaining fighter pilots has spurred interest in the
cost effectiveness of preventative and rehabilitative health solutions.METHODS: We investigated the potential cost effectiveness of a 5-yr, $24.9M U.S. preventative health program using equivalent annual worth (EAW) analysis. The program benefits were assessed with a combination
of actual and estimated medical cost data and projected pilot retention improvement rates. Sensitivity analysis of variables such as discount rate, medical cost avoidance, and pilot retention improvement rate was conducted.RESULTS: Annualized costs of approximately $5M U.S.
were used as the basis of comparison for annualized benefits. A medical cost database was searched to find expected annual direct medical (outpatient) costs related to injury of roughly $531K U.S. for the pilots covered by the program. Using Centers for Disease Control recommendations,
approximately $4.7M U.S. was estimated to be the annual work loss cost. The program would presumably reduce a significant portion of these annual costs, but not all. Assuming various proportions of reduced costs by the program, the EAW was found to be consistently negative. However,
when pilot retention improvement is included, EAW is positive using conservative assumptions.DISCUSSION: While outpatient and work loss costs will unlikely be completely covered by preventative health programs in this context, a minor improvement in pilot retention (about 1–3
additional retentions per year) produces a net positive annual benefit.Erneston CG, Fass RD, Ritschel JD, Cox AM. A preliminary analysis of the costs and benefits of physical therapy and strength training for fighter pilots. Aerosp Med Hum Perform. 2022; 93(8):637–642.
Kültürel Belleğin Aktarımında Zanaatkârlar: Safranbolu Demirciler Çarşısı Örneği
Authors: YAMAN Fatma Sena
Published: September 2022

Bir toplumdaki normlar, gelenekler, inanışlar ve yaşam biçimlerinin tümünü kapsayan kültür, ortak değerlere dair birliktelik içermektedir. Kültüre ait anlamlar dizisinin sonraki kuşaklara aktarımıyla oluşan kültürel bellek, sözlü kültür ve yazılı kültür ögeleriyle inşa edilmektedir. Tekrarlama, canlandırma ve hatırlama unsurlarıyla biçimlenerek atasözleri ve deyimlerle sürdürülen kültürel bellek, destanlar ve anılarla geçmişi bugüne bağlamakta, ritüellerle belirgin hale gelmektedir. Kentler, mekânsal ögeleri anısal olarak bünyesinde taşıyarak o toplumdaki hayat biçimi, sosyal ve ekonomik düzene dair imgeler barındırmaktadır. Kentin hafızası mekânsal unsurlarla nitelik kazanmakta, imgelerin taşıdıkları anlamlar itibarıyla farklı zaman dilimlerinde çeşitli tekrarlamalarla evirilerek diri tutulmaktadır. Türk kültüründe tarihsel süreç içerisinde çeşitli efsane, mit, inanış ve anlatılara konu olan demir, kültürel bellekteki mühim bir olgu olarak yer almakta ve kültürel belleğin aktarıcıları olarak demirciler usta-çırak ilişkisi dahilinde kültürel bellek aktarımını gerçekleştirmesi yönünden varlık göstermektedir. Başta demircilik olmak üzere birçok zanaata ev sahipliği yapan ve 1994‘te UNESCO Dünya Miras Listesi’ne alınan Safranbolu, kültürel belleğin temsili konusunda araştırma yapılacak bir kent sahasıdır. Çalışmada, 1796’da Safranbolu’da kurulan Demirciler Çarşısı’ndaki ustalarla görüşülerek demirin ve demircilerin Türk kültüründe taşıdığı ehemmiyet kültürel bellek bağlamında incelemiştir. Durum çalışması uygulanarak demircilerin ifade edegeldikleri unsurlar tetkik edilmiş, kültürel belleğin aktarıcıları olarak demircilerin zanaatlarını devam ettirdikleri çarşıda, meslek geleneklerini yeniden inşa süreciyle sağladıkları anlaşılmıştır.
Radical Right Populism and Immigration: Why Radical Right Populists are Anti-immigrationists?
Authors: ERAYMAN İbrahim Oğulcan
Published: September 2022

This study focuses on why radical right populists are anti-immigrationists and what would have been the main implications of this opposition. The emphasis on anti-immigration is crucial for radical right populism literature; almost every study points out xenophobia (in general) and anti-immigration (in particular) as characteristic features of radical right populism. This study aims to contribute to the literature on this field in two ways: First, by including recent issues, and second, by presenting the radical right populist perspectives’ opposition to immigration with a proposal of four-axis classification. Although this classification is not definitive, it would provide a systematic and holistic assessment of why radical right populism advocates an exclusionary approach, attitude, action, and policy towards immigrants. Within the scope of the study, this classification consists of crisis politics, election instrument, Islamization phobia and ressentiment dimensions. It has been concluded that with these four dimensions, if radical right populism’s anti-immigrant attitudes, actions and policies would become widespread among the local population and start to be expressed with louder voices, it would create an exclusionary, criminalizing and discriminatory atmosphere toward immigrants and refugees.
Of The Integration, Assimilation and Social Cohesion Terms, Turkey’s Choice
Authors: ALKAN AYKAÇ Songül , KARAKAŞ Mehmet
Published: September 2022

Along with a great immigration movements in recent years, Turkey has faced the problem of how do immigrants adopt to settled society. Considered as “foreigner” by settled society, immigrants have to deal with the problems of language, education, sheltering, health, finding job. Beside, unfamiliarity of socio-cultural values of settled society make their process of socialization difficult. Since integration is a frequently used term in biological and mechanical areas it has not become a favored term in definition of the relationship between settled society and immigrants. Assimilation, as any other stratgy is about relationship between immigrants and settled society, the rights which immigrants have and how will they position of their socio-cultural differences. However, Turkey has adopted the terms of neither integration nor assimilation to determine how will it build their existence in society. Turkey’s preference is using the term of “adaptation” and fictionalising strategies from the perspective of “social cohesion”. In this study, the terms of integration, assimilation and social cohesion will be discussed with literature review. Also, the meaning of Turkey’s choice on “social cohesion” for the process of immigrants’ integration and its own consolidation process will be evaluated.
Conceptualizing and Examining Dynamics in Communication Research
Authors: Brinberg Miriam , Lydon-Staley David M.
Published: September 2022

Communication research often focuses on processes of communication, such as how messages impact individuals over time or how interpersonal relationships develop and change. Despite their importance, the dynamics of these processes are often implicit in much theoretical and empirical work in communication. Intensive repeated measures data are becoming increasingly feasible to collect and, when coupled with appropriate analytic frameworks, enable researchers to better explore and articulate the dynamics underlying communication processes. To facilitate the study of dynamic processes, we (a) describe how intensive repeated measures data and analytic frameworks may be combined to articulate the dynamics of phenomena in communication research and (b) discuss considerations of dynamics when designing studies. We are excited about the future of dynamics in communication research, and we look forward to the iterations between empirical tests and theory revision that will occur as researchers delve into studying the dynamics of communication processes.
Feeling Out of Place: Who are the Non-Rural Rural Identifiers, and are They Unique Politically?
Authors: Lunz Trujillo Kristin
Published: September 2022

Previous work suggests rural identity stems from direct experience living in a rural area, and that categorical group membership occurs before social identification. However, some U.S. survey takers not living in a rural area indicate that being rural is part of their identity. Using an original survey of American adults, as well as 2019 and 2020 ANES data, I find that these non-rural rural identifiers are similar to rural identifiers in rural areas in terms of group-based affect and values, and are more right-leaning and populist than people who do not identify as rural (regardless of their location). Few consistent demographic differences between rural and non-rural rural identifiers exist. I conclude that non-rural rural identifiers have either been socialized as rural but moved away, or they affiliate with the values and norms of rural areas despite not categorically being part of the group, leading to rural identification.
Simultaneous pre-treatment of dietary Moringa oleifera leaf meal with polyethylene glycol and fibrolytic enzymes: Effect on growth performance, physiological indices, and meat quality parameters in jumbo quail
Authors: Mulaudzi Anzai , Mnisi Caven Mguvane , Mlambo Victor
Published: September 2022

The utility of Moringa oleifera leaf meal (MOLM) as a source of biologically active substances and nutrients for Jumbo quail is limited by high concentrations of condensed tannins and fiber. Simultaneous application of polyethylene glycol (PEG), a tannin-binding compound, and exogenous fibrolytic multi-enzymes could ameliorate antinutritional effects of condensed tannins and fiber thus improving MOLM utilization in quail diets. This study investigated the effect of pre-treating dietary MOLM with PEG and fibrolytic enzymes on live performance, blood parameters, visceral organs, and carcass and meat quality characteristics in Jumbo quail. A total of 381, two-week-old quail chicks (57.5 ± 3.95 g live-weight) were randomly distributed to six dietary treatments replicated six times. The treatments were: T1 = a standard grower diet containing untreated MOLM (10%); T2 = a standard grower diet containing MOLM (10%) pre-treated with 5.4% PEG; and a standard grower diet containing MOLM (10%) pre-treated with 5.4% PEG and 1.25% (T3), 1.50% (T4), 1.75% (T5) and 2.0% (T6) fibrolytic multi-enzymes. Graded levels of enzymes did not induce linear or quadratic effects for overall feed intake, feed conversion efficiency, hematological, carcass, and meat quality parameters in response to increasing fibrolytic enzyme levels. However, weight gain in week 3 quadratically responded [R2 = 0.117, P = 0.043]. Three-week old birds reared on T3 had lower (p < 0.05) weight gains (40.9 g/bird) than those reared on the other treatment groups. Birds reared on T6 diet had longer caecum (14.1 cm) than those reared on T2, T3, T4 and T5 whose caeca lengths did not differ (P > 0.05). Birds reared on diet T5 had shorter small intestines (59.5 cm) than those reared on T1 and T2 diets. It can be concluded that simultaneous pre-treatment of dietary MOLM with PEG and fibrolytic enzymes did not improve live performance, blood parameters, and carcass and meat quality traits, but affected some visceral organ sizes in Jumbo quail.
Fibroblast-derived CXCL12 increases vascular permeability in a 3-D microfluidic model independent of extracellular matrix contractility
Authors: Holter Jacob C. , Chang Chia-Wen , Avendano Alex , Garg Ayush A. , Verma Ajeet K. , Charan Manish , Ahirwar Dinesh K. , Ganju Ramesh K. , Song Jonathan W.
Published: September 2022

Cancer-associated fibroblasts (CAFs) play an active role in remodeling the local tumor stroma to support tumor initiation, growth, invasion, metastasis, and therapeutic resistance. The CAF-secreted chemokine, CXCL12, has been directly implicated in the tumorigenic progression of carcinomas, including breast cancer. Using a 3-D in vitro microfluidic-based microtissue model, we demonstrate that stromal CXCL12 secreted by CAFs has a potent effect on increasing the vascular permeability of local blood microvessel analogues through paracrine signaling. Moreover, genetic deletion of fibroblast-specific CXCL12 significantly reduced vessel permeability compared to CXCL12 secreting CAFs within the recapitulated tumor microenvironment (TME). We suspected that fibroblast-mediated extracellular matrix (ECM) remodeling and contraction indirectly accounted for this change in vessel permeability. To this end, we investigated the autocrine effects of CXCL12 on fibroblast contractility and determined that antagonistic blocking of CXCL12 did not have a substantial effect on ECM contraction. Our findings indicate that fibroblast-secreted CXCL12 has a significant role in promoting a leakier endothelium hospitable to angiogenesis and tumor cell intravasation; however, autocrine CXCL12 is not the primary upstream trigger of CAF contractility.
Gelatin-methacryloyl hydrogels containing turnip mosaic virus for fabrication of nanostructured materials for tissue engineering
Authors: González-Gamboa Ivonne , Velázquez-Lam Edith , Lobo-Zegers Matías José , Frías-Sánchez Ada Itzel , Tavares-Negrete Jorge Alfonso , Monroy-Borrego Andrea , Menchaca-Arrendondo Jorge Luis , Williams Laura , Lunello Pablo , Ponz Fernando , Alvarez Mario Moisés , Trujillo-de Santiago Grissel
Published: September 2022

Current tissue engineering techniques frequently rely on hydrogels to support cell growth, as these materials strongly mimic the extracellular matrix. However, hydrogels often need ad hoc customization to generate specific tissue constructs. One popular strategy for hydrogel functionalization is to add nanoparticles to them. Here, we present a plant viral nanoparticle the turnip mosaic virus (TuMV), as a promising additive for gelatin methacryloyl (GelMA) hydrogels for the engineering of mammalian tissues. TuMV is a flexuous, elongated, tubular protein nanoparticle (700–750 nm long and 12–15 nm wide) and is incapable of infecting mammalian cells. These flexuous nanoparticles spontaneously form entangled nanomeshes in aqueous environments, and we hypothesized that this nanomesh structure could serve as a nanoscaffold for cells. Human fibroblasts loaded into GelMA-TuMV hydrogels exhibited similar metabolic activity to that of cells loaded in pristine GelMA hydrogels. However, cells cultured in GelMA-TuMV formed clusters and assumed an elongated morphology in contrast to the homogeneous and confluent cultures seen on GelMA surfaces, suggesting that the nanoscaffold material per se did not favor cell adhesion. We also covalently conjugated TuMV particles with epidermal growth factor (EGF) using a straightforward reaction scheme based on a Staudinger reaction. BJ cells cultured on the functionalized scaffolds increased their confluency by approximately 30% compared to growth with unconjugated EGF. We also provide examples of the use of GelMA-TuMV hydrogels in different biofabrication scenarios, include casting, flow-based-manufacture of filaments, and bioprinting. We envision TuMV as a versatile nanobiomaterial that can be useful for tissue engineering.
Advantages of CRISPR-Cas9 combined organoid model in the study of congenital nervous system malformations
Authors: Xiaoshuai Li , Qiushi Wang , Rui Wang
Published: September 2022

In the past 10 years, gene-editing and organoid culture have completely changed the process of biology. Congenital nervous system malformations are difficult to study due to their polygenic pathogenicity, the complexity of cellular and neural regions of the brain, and the dysregulation of specific neurodevelopmental processes in humans. Therefore, the combined application of CRISPR-Cas9 in organoid models may provide a technical platform for studying organ development and congenital diseases. Here, we first summarize the occurrence of congenital neurological malformations and discuss the different modeling methods of congenital nervous system malformations. After that, it focuses on using organoid to model congenital nervous system malformations. Then we summarized the application of CRISPR-Cas9 in the organoid platform to study the pathogenesis and treatment strategies of congenital nervous system malformations and finally looked forward to the future.
Achieving spatially precise diagnosis and therapy in the mammalian gut using synthetic microbial gene circuits
Authors: Robinson Clare M. , Short Nina E. , Riglar David T.
Published: September 2022

The mammalian gut and its microbiome form a temporally dynamic and spatially heterogeneous environment. The inaccessibility of the gut and the spatially restricted nature of many gut diseases translate into difficulties in diagnosis and therapy for which novel tools are needed. Engineered bacterial whole-cell biosensors and therapeutics have shown early promise at addressing these challenges. Natural and engineered sensing systems can be repurposed in synthetic genetic circuits to detect spatially specific biomarkers during health and disease. Heat, light, and magnetic signals can also activate gene circuit function with externally directed spatial precision. The resulting engineered bacteria can report on conditions in situ within the complex gut environment or produce biotherapeutics that specifically target host or microbiome activity. Here, we review the current approaches to engineering spatial precision for in vivo bacterial diagnostics and therapeutics using synthetic circuits, and the challenges and opportunities this technology presents.
Investigation of metabolic crosstalk between host and pathogenic Clostridioides difficile via multiomics approaches
Authors: Kwon Ji-Eun , Jo Sung-Hyun , Song Won-Suk , Lee Jae-Seung , Jeon Hyo-Jin , Park Ji-Hyeon , Kim Ye-Rim , Baek Ji-Hyun , Kim Min-Gyu , Kwon Seo-Young , Kim Jae-Seok , Yang Yung-Hun , Kim Yun-Gon
Published: September 2022

Clostridioides difficile is a gram-positive anaerobic bacterium that causes antibiotic-associated infections in the gut. C. difficile infection develops in the intestine of a host with an imbalance of the intestinal microbiota and, in severe cases, can lead to toxic megacolon, intestinal perforation, and even death. Despite its severity and importance, however, the lack of a model to understand host-pathogen interactions and the lack of research results on host cell effects and response mechanisms under C. difficile infection remain limited. Here, we developed an in vitro anaerobic-aerobic C. difficile infection model that enables direct interaction between human gut epithelial cells and C. difficile through the Mimetic Intestinal Host–Microbe Interaction Coculture System. Additionally, an integrative multiomics approach was applied to investigate the biological changes and response mechanisms of host cells caused by C. difficile in the early stage of infection. The C. difficile infection model was validated through the induction of disaggregation of the actin filaments and disruption of the intestinal epithelial barrier as the toxin-mediated phenotypes following infection progression. In addition, an upregulation of stress-induced chaperones and an increase in the ubiquitin proteasomal pathway were identified in response to protein stress that occurred in the early stage of infection, and downregulation of proteins contained in the electron transfer chain and ATP synthase was observed. It has been demonstrated that host cell energy metabolism is inhibited through the glycolysis of Caco-2 cells and the reduction of metabolites belonging to the TCA cycle. Taken together, our C. difficile infection model suggests a new biological response pathway in the host cell induced by C. difficile during the early stage of infection at the molecular level under anaerobic-aerobic conditions. Therefore, this study has the potential to be applied to the development of future therapeutics through basic metabolic studies of C. difficile infection.
Controlled Release of Therapeutics From Enzyme-Responsive Biomaterials
Authors: Minehan Rachel L. , Del Borgo Mark P.
Published: September 2022

Numerous promising drug leads are regularly abandoned due to having poor pharmacokinetic profiles. Biomaterials are often used as drug delivery systems to improve the pharmacokinetics of these otherwise promising drug candidates. Hydrogels are a subset of biomaterials that offer porous matrices, permeable to endogenous nutrients in aqueous in vivo environments. Environmentally sensitive hydrogels have become of interest to further tailor these materials to only allow therapeutic release in response to specific environmental cues instead of simple encapsulation and subsequent diffusion. Enzyme-responsive materials allow for the exploitation of endogenous tissue enzyme expression levels and/or altered expression levels during pathological states. The simplest and most common method for stimulus-dependant release is through the destruction of the matrix to release encapsulated therapeutics that would otherwise be trapped indefinitely. A second approach is to covalently attach therapeutics to the hydrogel scaffold and include enzymatically sensitive cross linkages throughout the scaffold backbone. The third, and least common approach, is to use labile linkers between the therapeutic and the scaffold which affords controlled, precise release of the therapeutic with a known molecular structure. These linkers can also be tailored to specific enzymes that are elevated in certain disease states. This review will; 1) briefly describe matrix degradation; 2) present the cleavage of covalently attached therapeutics and; 3) highlight the few examples of targeted cleavage of therapeutics from specific matrix locations and the potential use of these systems in biomedicine.
PROTACs: The Future of Leukemia Therapeutics
Authors: Anwar Zubair , Ali Muhammad Shahzad , Galvano Antonio , Perez Alessandro , La Mantia Maria , Bukhari Ihtisham , Swiatczak Bartlomiej
Published: September 2022

The fight to find effective, long-lasting treatments for cancer has led many researchers to consider protein degrading entities. Recent developments in PROteolysis TArgeting Chimeras (PROTACs) have signified their potential as possible cancer therapies. PROTACs are small molecule, protein degraders that function by hijacking the built-in Ubiquitin-Proteasome pathway. This review mainly focuses on the general design and functioning of PROTACs as well as current advancements in the development of PROTACs as anticancer therapies. Particular emphasis is given to PROTACs designed against various types of Leukemia/Blood malignancies.
Inhibiting DNA methylation as a strategy to enhance adipose-derived stem cells differentiation: Focus on the role of Akt/mTOR and Wnt/β-catenin pathways on adipogenesis
Authors: Ceccarelli S. , Gerini G. , Megiorni F. , Pontecorvi P. , Messina E. , Camero S. , Anastasiadou E. , Romano E. , Onesti M. G. , Napoli C. , Marchese C.
Published: September 2022

Adipose-derived mesenchymal stem cells (ASCs) represent a valid therapeutic option for clinical application in several diseases, due to their ability to repair damaged tissues and to mitigate the inflammatory/immune response. A better understanding of the underlying mechanisms regulating ASC biology might represent the chance to modulate their in vitro characteristics and differentiation potential for regenerative medicine purposes. Herein, we investigated the effects of the demethylating agent 5-azacytidine (5-aza) on proliferation, clonogenicity, migration, adipogenic differentiation and senescence of ASCs, to identify the molecular pathways involved. Through functional assays, we observed a detrimental effect of 5-aza on ASC self-renewal capacity and migration, accompanied by actin cytoskeleton reorganization, with decreased stress fibers. Conversely, 5-aza treatment enhanced ASC adipogenic differentiation, as assessed by lipid accumulation and expression of lineage-specific markers. We analyzed the involvement of the Akt/mTOR, MAPK and Wnt/β-catenin pathways in these processes. Our results indicated impairment of Akt and ERK phosphorylation, potentially explaining the reduced cell proliferation and migration. We observed a 5-aza-mediated inhibition of the Wnt signaling pathway, this potentially explaining the pro-adipogenic effect of the drug. Finally, 5-aza treatment significantly induced ASC senescence, through upregulation of the p53/p21 axis. Our data may have important translational implications, by helping in clarifying the potential risks and advantages of using epigenetic treatment to improve ASC characteristics for cell-based clinical approaches.
Assessing kidney development and disease using kidney organoids and CRISPR engineering
Authors: Safi Wajima , Marco Andrés , Moya Daniel , Prado Patricia , Garreta Elena , Montserrat Nuria
Published: September 2022

The differentiation of human pluripotent stem cells (hPSCs) towards organoids is one of the biggest scientific advances in regenerative medicine. Kidney organoids have not only laid the groundwork for various organ-like tissue systems but also provided insights into kidney embryonic development. Thus, several protocols for the differentiation of renal progenitors or mature cell types have been established. Insights into the interplay of developmental pathways in nephrogenesis and determination of different cell fates have enabled the in vitro recapitulation of nephrogenesis. Here we first provide an overview of kidney morphogenesis and patterning in the mouse model in order to dissect signalling pathways that are key to define culture conditions sustaining renal differentiation from hPSCs. Secondly, we also highlight how genome editing approaches have provided insights on the specific role of different genes and molecular pathways during renal differentiation from hPSCs. Based on this knowledge we further review how CRISPR/Cas9 technology has enabled the recapitulation and correction of cellular phenotypes associated with human renal disease. Last, we also revise how the field has positively benefited from emerging technologies as single cell RNA sequencing and discuss current limitations on kidney organoid technology that will take advantage from bioengineering solutions to help standardizing the use of this model systems to study kidney development and disease.
Exercise training ameliorates myocardial phenotypes in heart failure with preserved ejection fraction by changing N6-methyladenosine modification in mice model
Authors: Liu Kai , Ju Wenhao , Ouyang Shengrong , Liu Zhuo , He Feng , hao Jingyi , Guan Hongyan , Wu Jianxin
Published: September 2022

Heart failure with preserved ejection fraction (HFpEF) shows complicated and not clearly defined etiology and pathogenesis. Although no pharmacotherapeutics have improved the survival rate in HFpEF, exercise training has become an efficient intervention to improve functional outcomes. Here, we investigated N6-methyladenosine (m6A) RNA methylation modification in a “two-hit” mouse model with HFpEF and HFpEF with exercise (HFpEF + EXT). The manner of m6A in HFpEF and HFpEF + EXT hearts was explored via m6A-specific methylated RNA immunoprecipitation followed by high-throughput and RNA sequencing methods. A total amount of 3992 novel m6A peaks were spotted in HFpEF + EXT, and 426 differently methylated sites, including 371 hypermethylated and 55 hypomethylated m6A sites, were singled out for further analysis (fold change >2, p < 0.05). According to gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses, unique m6A-modified transcripts in HFpEF + EXT were associated with apoptosis-related pathway and myocardial energy metabolism. HFpEF + EXT had higher total m6A levels and downregulated fat mass and obesity-related (FTO) protein levels. Overexpression of FTO cancels out the benefits of exercise in HFpEF + EXT mice by promoting myocyte apoptosis, myocardial fibrosis and myocyte hypertrophy. Totally, m6A is a significant alternation of epitranscriptomic processes, which is also a potentially meaningful therapeutic target.
Not sorcery after all: Roles of multiple charged residues in membrane insertion of gasdermin-A3
Authors: Korn Viktoria , Pluhackova Kristyna
Published: September 2022

Gasdermins execute programmatory cell death, known as pyroptosis, by forming medium-sized membrane pores. Recently, the molecular structure of those pores as well as the diversity in their shape and size have been revealed by cryoTEM and atomic force microscopy, respectively. Even though a growth of smaller to larger oligomers and reshaping from slits to rings could be documented, the initiation of the gasdermin pore formation remains a mystery. In one hypothesis, gasdermin monomers insert into membranes before associating into oligomeric pores. In the other hypothesis, gasdermin oligomers preassemble on the membrane surface prior to membrane insertion. Here, by studying the behavior of monomeric membrane-inserted gasdermin-A3 (GSDMA3), we unveil that a monomeric gasdermin prefers the membrane-adsorbed over the membrane-inserted state. Our results thus support the hypothesis of oligomers preassembling on the membrane surface before membrane penetration. At the same time, our simulations of small membrane-inserted arcs of GSDMA3 suggest that the inserting oligomer can be small and does not have to comprise a full ring of approximately 26–30 subunits. Moreover, our simulations have revealed an astonishingly large impact of salt-bridge formation and protein surroundings on the transmembrane passage of charged residues, reducing the energetic cost by up to 53% as compared to their free forms. The here observed free energy barrier of mere 5.6 kcal/mol for the membrane insertion of monomeric GSDMA3 explains the surprising ability of gasdermins to spontaneously self-insert into cellular membranes.
Identification of novel lactate metabolism signatures and molecular subtypes for prognosis in hepatocellular carcinoma
Authors: Guan Qiutong , Pan Jing , Ren Ninghui , Qiao Chu , Wei Minjie , Li Zhenhua
Published: September 2022

Background: Evidence has shown that lactate, an immune signaling molecule, is associated with hepatocellular carcinoma (HCC) progression and immune suppression. Therefore, identifying lactate metabolism-related molecules is a promising therapeutic strategy to inhibit the development of HCC and overcome chemotherapy resistance. Long noncoding RNAs (lncRNAs) are related to tumorigenesis and metastasis. Hence, verifying the molecular subtypes of lncRNAs related to lactate metabolism will play a critical role in managing HCC.

Methods: Based on HCC data in The Cancer Genome Atlas (TCGA), lactate metabolic pathway-related genes were enriched by gene collection and enrichment analysis (GSEA). Lactate metabolism-related lncRNAs (LM_lncRNAs) were identified by correlation analysis, HCC molecular subtypes were determined using nonnegative matrix factorization (NMF) clustering, and the response of the three subtypes to chemotherapeutics was further evaluated using the Genomic Tumor Sensitive Cell Line (GDSC) dataset. LM_lncRNAs were examined via Lasso-Cox regression analysis to determine prognosis for patients. A Nomagram plot was used to predict patient survival time.

Results: Three molecular subtypes of HCC were identified. The survival rate of patients with C1 subtype was higher than that of those with C2 and C3. Additionally, patients with C3 subtype have higher levels of immune cell infiltration and high expression of genes related to immune checkpoints. The GDSC results indicated that patients with C3 subtypes were more sensitive to chemotherapy drugs such as sorafenib and sunitinib. The prognostic risk assessment model consisted of six risk factors (AC034229.4, AC131009.1, MYOSLID, AC008667.1, AC012073.1, AC068025.1) and two protective factors (LINC00402 and AC103858.1). Based on Kaplan-Meier analysis, low-risk HCC patients had a high survival rate, and the receiver operating characteristic curve (ROC), calibration curve, and C-index confirmed good prediction ability.

Conclusion: In this study, the molecular subtyping method and prediction model of lactate metabolism-related lncRNAs (LM_lncRNAs) were constructed for the prognosis of HCC patients. This work demonstrated the potential targets of LM_lncRNAs and provided a novel perspective and therapeutic paradigm for future clinical translation.
The ribosome inhibitor chloramphenicol induces motility deficits in human spermatozoa: A proteomic approach identifies potentially involved proteins
Authors: Bisconti Marie , Leroy Baptiste , Gallagher Meurig T. , Senet Coralie , Martinet Baptiste , Arcolia Vanessa , Wattiez Ruddy , Kirkman-Brown Jackson C. , Simon Jean-François , Hennebert Elise
Published: September 2022

Mature spermatozoa are almost completely devoid of cytoplasm; as such it has long been believed that they do not contain ribosomes and are therefore not capable of synthesising proteins. However, since the 1950s, various studies have shown translational activity within spermatozoa, particularly during their in vitro capacitation. But the type of ribosomes involved (cytoplasmic or mitochondrial) is still debated. Here, we investigate the presence and activity of the two types of ribosomes in mature human spermatozoa. By targeting ribosomal RNAs and proteins, we show that both types of ribosomes are localized in the midpiece as well as in the neck and the base of the head of the spermatozoa. We assessed the impact of cycloheximide (CHX) and chloramphenicol (CP), inhibitors of cytoplasmic and mitochondrial ribosomes, respectively, on different sperm parameters. Neither CHX, nor CP impacted sperm vitality, mitochondrial activity (measured through the ATP content), or capacitation (measured through the content in phosphotyrosines). However, increasing CP concentrations induced a decrease in total and progressive motilities as well as on some kinematic parameters while no effect was observed with CHX. A quantitative proteomic analysis was performed by mass spectrometry in SWATH mode to compare the proteomes of spermatozoa capacitated in the absence or presence of the two ribosome inhibitors. Among the ∼700 proteins identified in the different tested conditions, 3, 3 and 25 proteins presented a modified abundance in the presence of 1 and 2 mg/ml of CHX, and 1 mg/ml of CP, respectively. The observed abundance variations of some CP-down regulated proteins were validated using Multiple-Reaction Monitoring (MRM). Taken together, our results are in favor of an activity of mitochondrial ribosomes. Their inhibition by CP results in a decrease in the abundance of several proteins, at least FUNDC2 and QRICH2, and consequently induces sperm motility deficits.
Enhancing autophagy and energy metabolism in the meniscus can delay the occurrence of PTOA in ACLT rat
Authors: Zhu Huangrong , Liu Hai , Chen Xizhong , Xu Xin , Zhang Shuqin , Xie Denghui
Published: September 2022

Osteoarthritis (OA) is a progressive degenerative joint disease characterized by the destruction of the articular cartilage, meniscus and the like. Autophagy and cellular energy metabolism are the mechanisms by which cells maintain homeostasis. However, little is known about the effects of autophagy and cellular energy metabolism on meniscus degeneration, and the pathogenesis of posttraumatic osteoarthritis (PTOA) after the meniscal injury is rarely reported. Therefore, this study aimed to investigate the relationship between changes in autophagy and cellular energy metabolism in the meniscus following anterior cruciate ligament transection (ACLT) and PTOA induced by subsequent articular cartilage injury. In this study, we use a combination of cell experiments in vitro and animal experiments in vivo. On the one hand, cell experiment results show that inhibiting the mTORC1 signaling pathway by inhibiting the phosphorylation of S6K and AKT proteins in meniscal cells will lead to the increase of Beclin1, LC-3B, ATG12, ULK1, P62, and activate autophagy-related signaling pathways, which in turn protects the extracellular matrix component COL1 of meniscal cells from degradation by catabolic factor MMP13. In addition, it increased the generation of mitochondrial membrane potential in meniscal cells, increased the expression of anti-apoptotic factor BCL-XL, decreased the expression of pro-apoptotic factors BAD and BAX, and reduced the apoptosis of meniscal cells. More importantly, under the stimulation of inflammatory factor IL-1β, the secretion of meniscus cells can reduce the elevated levels of MMP13 and Adamts5 caused by chondrocytes affected by IL-1β. On the other hand, the results of animal experiments in vivo further proved the validity of the results of the cell experiments, and also proved that the meniscus injury did prior to the articular cartilage degeneration after ACLT. In conclusion, this study suggests that the meniscus prior to articular cartilage damage during the development of PTOA after ACLT, and that promoting autophagy and energy metabolism of meniscal cells may be a potential therapeutic target for delaying PTOA.
Cooperative bundling by fascin generates actin structures with architectures that depend on filament length
Authors: Sherer Laura A. , Courtemanche Naomi
Published: September 2022

The assembly of actin-based structures with precisely defined architectures supports essential cellular functions, including motility, intracellular transport, and division. The geometric arrangements of the filaments within actin structures are stabilized via the association of crosslinking proteins, which bind two filaments simultaneously. Because actin polymerization and crosslinking occur concurrently within the dynamic environment of the cell, these processes likely play interdependent roles in shaping the architectures of actin-based structures. To dissect the contribution of polymerization to the construction of higher-order actin structures, we investigated how filament elongation affects the formation of simple, polarized actin bundles by the crosslinking protein fascin. Using populations of actin filaments to represent distinct stages of elongation, we found that the rate of bundle assembly increases with filament length. Fascin assembles short filaments into discrete bundles, whereas bundles of long filaments merge with one another to form interconnected networks. Although filament elongation promotes bundle coalescence, many connections formed between elongating bundles are short-lived and are followed by filament breakage. Our data suggest that initiation of crosslinking early in elongation aligns growing filaments, creating a template for continued bundle assembly as elongation proceeds. This initial alignment promotes the assembly of bundles that are resistant to large changes in curvature that are required for coalescence into interconnected networks. As a result, bundles of short filaments remain straighter and more topologically discrete as elongation proceeds than bundles assembled from long filaments. Thus, uncoordinated filament elongation and crosslinking can alter the architecture of bundled actin networks, highlighting the importance of maintaining precise control over filament length during the assembly of specialized actin structures.
Annexin A2 and Kidney Diseases
Authors: Lin Ling , Hu Kebin
Published: September 2022

Annexin A2 is a Ca2+- and phospholipid-binding protein which is widely expressed in various types of cells and tissues. As a multifunctional molecule, annexin A2 is found to be involved in diverse cell functions and processes, such as cell exocytosis, endocytosis, migration and proliferation. As a receptor of plasminogen and tissue plasminogen activator, annexin A2 promotes plasmin generation and regulates the homeostasis of blood coagulation, fibrinolysis and matrix degradation. As an antigen expressed on cell membranes, annexin A2 initiates local inflammation and damage through binding to auto-antibodies. Annexin A2 also mediates multiple signaling pathways induced by various growth factors and oxidative stress. Aberrant expression of annexin A2 has been found in numerous kidney diseases. Annexin A2 has been shown to act as a co-receptor of integrin CD11b mediating NF-kB-dependent kidney inflammation, which is further amplified through annexin A2/NF-kB-triggered macrophage M2 to M1 phenotypic change. It also modulates podocyte cytoskeleton rearrangement through Cdc42 and Rac1/2/3 Rho pathway causing proteinuria. Thus, annexin A2 is implicated in the pathogenesis and progression of various kidney diseases. In this review, we focus on the current understanding of the role of annexin A2 in kidney diseases.
Large and stable: actin aster networks formed via entropic forces
Authors: Spukti Friedrich Fabian , Schnauß Jörg
Published: September 2022

Biopolymer networks play a major role as part of the cytoskeleton. They provide stable structures and act as a medium for signal transport. These features encourage the application of such networks as organic computation devices. While research on this topic is not advanced yet, previous results are very promising. The protein actin in particular appears advantageous. It can be arranged to various stable structures and transmit several signals. In this study aster shaped networks were self-assembled via entropic forces by the crowding agent methyl cellulose. These networks are characterised by a regular and uniquely thick bundle structure, but have so far only been accounted in droplets of 100 μm diameter. We report now regular asters in an area of a few mm2 that could be observed even after months. Such stability outside of an organism is striking and underlines the great potential actin aster networks display.
Carbon-encapsulated V2O3 nanorods for high-performance aqueous Zn-ion batteries
Authors: Hao Ziyi , Jiang Weikang , Zhu Kaiyue
Published: September 2022

Searching for stable cathodes is of paramount importance to the commercial development of low-cost and safe aqueous Zn-ion batteries (AZIBs). V2O3 is a good candidate for AZIB cathodes but has unsatisfied cycling stability. Herein, we solve the stability issue of a V2O3 cathode by coating a robust carbon shell. Strong evidence was provided that V2O3 was oxidized to favorable V2O5·nH2O during charging and the carbon shell could promote the oxidation of V2O3 to V2O5·nH2O. The discharge capacity was increased from ∼45 mA h g−1 to 336 mA h g−1 after V2O3 was oxidized to V2O5·nH2O, indicating a higher Zn2+-storage capability of V2O5·nH2O than V2O3. In addition, the rate-capability and long-term cycling performance are greatly enhanced after coating carbon shells on the surface of V2O3 nanorods. Therefore, the presented strategy of introducing carbon shells and fundamental insights into the favorable role of carbon shells in this study contribute to the advancement of highly stable AZIBs.
Functionalized UiO-66-NH2 by trimellitic acid for highly selective adsorption of basic blue 3 from aqueous solutions
Authors: Wang Tingting , Han Lin , Li Xin , Chen Tianen , Wang Shifeng
Published: September 2022

A novel metal-organic framework (MOF) UiO-66-TLA (UiO-66-Trimellitic Acid) was synthesized by one-pot method with trimellitic acid as modifier, which can effectively remove the basic dye Basic Blue 3 (BB3) in wastewater. Modification with carboxyl groups facilitates the adsorption of the cationic dye Basic Blue 3. The adsorption of BB3 by the modified UiO-66-TLA was significantly greater than that of its parent MOF. The adsorption capacity of the modified UiO-66-TLA for BB3 (234.23 mg g−1) was 93.2% higher than that of the original UiO-66-NH2 (121.24 mg g−1), this is closely related to the electrostatic interaction of -COOH in trimellitic acid. UiO-66-TLA was successfully synthesized as indicated by various characterization results. The adsorption kinetics conformed to the pseudo-second-order model, and the adsorption isotherm conformed to the Redlich-Peterson isotherm. This indicates that BB3 is a multi-parameter model of monolayer/multilayer arrangement on the adsorbent surface, and its rate-controlling step is chemisorption. The adsorption process was non-spontaneous and belonged to an endothermic reaction, in addition, it has great adsorption stability and regeneration The interaction of the modified UiO-66-TLA with BB3 was mainly affected by mechanisms, such as electrostatic interaction, π–π stacking as well as the abundant functional groups on UiO-66-TLA surface. These results demonstrate that UiO-66-TLA is an efficient, regenerable, water-stable material for the removal of BB3 in solution, with practical implications, suggesting its potential as a dye adsorbent.
Impact of gut microbiome on dyslipidemia in japanese adults: Assessment of the Shika-machi super preventive health examination results for causal inference
Authors: Miyajima Yuna , Karashima Shigehiro , Ogai Kazuhiro , Taniguchi Kouki , Ogura Kohei , Kawakami Masaki , Nambo Hidetaka , Kometani Mitsuhiro , Aono Daisuke , Demura Masashi , Yoneda Takashi , Tsujiguchi Hiromasa , Hara Akinori , Nakamura Hiroyuki , Okamoto Shigefumi
Published: September 2022

Dyslipidemia (DL) is one of the most common lifestyle-related diseases. There are few reports showing the causal relationship between gut microbiota (GM) and DL. In the present study, we used a linear non-Gaussian acyclic model (LiNGAM) to evaluate the causal relationship between GM and DL. A total of 79 men and 82 women aged 40 years or older living in Shika-machi, Ishikawa Prefecture, Japan were included in the analysis, and their clinical information was investigated. DNA extracted from the GM was processed to sequence the 16S rRNA gene using next-generation sequencing. Participants were divided into four groups based on sex and lipid profile information. The results of one-way analysis of covariance, linear discriminant analysis effect size, and least absolute value reduction and selection operator logistic regression model indicated that several bacteria between men and women may be associated with DL. The LiNGAM showed a presumed causal relationship between different bacteria and lipid profiles in men and women. In men, Prevotella 9 and Bacteroides were shown to be potentially associated with changes in low- and high-density lipoprotein cholesterol levels. In women, the LiNGAM results showed two bacteria, Akkermansia and Escherichia/Shigella, had a presumptive causal relationship with lipid profiles. These results may provide a new sex-based strategy to reduce the risk of developing DL and to treat DL through the regulation of the intestinal environment using specific GM.