bluuebunny/crossref_metadata_2025 huggingface dataset:
Modelos de negocio para el periodismo: una propuesta metodológica para realizar estudios de caso
Authors: Marín Sanchiz Cristian Ramón , Carvajal Prieto Miguel
Published: July 2021

La dificultad de la industria periodística para crear modelos de negocio sostenibles en el contexto digital es una asignatura pendiente. Desde el campo de la investigación en periodismo se ha atendido este problema con estudios de casos o visiones panorámicas, pero sin adoptar una perspectiva holística ni concebir el modelo de negocio como un sistema de creación de valor, más que de ingresos. Ante esta situación, el presente artículo ofrece una revisión bibliográfica sistematizada que confirma la falta de estandarización en los estudios de caso, que han otorgado un excesivo protagonismo a las fuentes de ingresos sin profundizar en factores clave para el éxito de un modelo de negocio, como la propuesta de valor. Para contribuir a la resolución de esta problemática se realiza una propuesta metodológica que permitirá analizar modelos de negocio de empresas mediáticas de una forma integral y estandarizada, una vía para establecer mejores comparaciones entre distintas empresas, comprender las claves que hacen sostenibles las iniciativas periodísticas y generar un incremento de la innovación y el intercambio de conocimiento.
El reportaje de historias de vida como punto de partida de la radio dramatizada y el 'podcast' de no ficción en el ecosistema digital. Estudio de caso: 'Sin mi identidad' (Cadena COPE), 'Lo conocí en un Corpus' (Podium Podcast) y 'Las tres muertes de mi padre' (Cuonda).
Authors: Martínez-Otón Laura , Rodríguez-Luque Cristina , Alcudia-Borreguero Mario
Published: July 2021

En el ecosistema digital actual el sonido está alcanzando protagonismo a través de nuevos formatos como el podcasting, nacidos en la era de la movilidad. Formatos que pueden compartir elementos, características, dinámicas de trabajo y consumo con otros formatos tradicionalmente radiofónicos, como el reportaje, el docudrama o la radionovela. En este artículo se pretende analizar si la fuerza del human reach storytelling es un punto de partida común en los reportajes analógicos y en los podcasts de ficción y no ficción, tanto en plataformas de audio como en la radio convencional. Para ello, se plantea el estudio de caso de tres podcasts: ‘Sin mi identidad’ (2018, Cadena COPE), ‘Lo conocí en un Corpus’ (2017, Podium Podcast) y ‘Las tres muertes de mi padre’ (2017, Cuonda). La metodología utilizada es cualitativa descriptiva e incluye entrevistas semiestructuradas con sujetos clave en el proceso de los tres espacios objeto de estudio. En los casos analizados se puede afirmar que, si bien el reportaje y el podcast de ficción y no ficción son productos sonoros diferentes, comparten similitudes de producción, documentación y grabación. Asimismo, todos tienen como punto de partida común una historia real, incluso cuando el podcast es de ficción.
First record of Phyllocoptruta musae (Acari: Prostigmata: Eriophyidae) in the Neotropics, in Hispaniola
Authors: Gómez-Moya Cristina A. , Amrine James W. , Flechtmann Carlos H.W. , Campos Dionicio , Navia Denise , Suárez Pablo
Published: July 2021

The banana rust mite, Phyllocoptruta musae Keifer, is reported for the first time from the Neotropics, in the Dominican Republic. The current known distribution of this pest is provided. Comparisons are made to other Neotropical species of Phyllocoptruta genus, and descriptions with photos are provided of the injury to plants.
Oligoquetofagia por Anolis sagrei y nectarivoría por Anolis porcatus (Squamata: Dactyloidae): nuevas observaciones
Authors: De Armas Luis F.
Published: July 2021

Nuevas observaciones de campo confirman que la ingestión de lombrices de tierra (Oligochaeta) por Anolis sagrei no es un evento tan raro como se creía. De igual modo, las observaciones realizadas en tres inviernos consecutivos (2019, 2020, 2021), durante la temporada de floración de las orquídeas Cattleya lueddemanniana y Guarianthe skinneri, ratifican que la nectarivoría es un hábito regular en Anolis porcatus.
Synchronization in Networks With Heterogeneous Adaptation Rules and Applications to Distance-Dependent Synaptic Plasticity
Authors: Berner Rico , Yanchuk Serhiy
Published: July 2021

This work introduces a methodology for studying synchronization in adaptive networks with heterogeneous plasticity (adaptation) rules. As a paradigmatic model, we consider a network of adaptively coupled phase oscillators with distance-dependent adaptations. For this system, we extend the master stability function approach to adaptive networks with heterogeneous adaptation. Our method allows for separating the contributions of network structure, local node dynamics, and heterogeneous adaptation in determining synchronization. Utilizing our proposed methodology, we explain mechanisms leading to synchronization or desynchronization by enhanced long-range connections in nonlocally coupled ring networks and networks with Gaussian distance-dependent coupling weights equipped with a biologically motivated plasticity rule.
Cancer-Associated Fibroblast (CAF) Heterogeneity and Targeting Therapy of CAFs in Pancreatic Cancer
Authors: Geng Xinglong , Chen Hongze , Zhao Liang , Hu Jisheng , Yang Wenbo , Li Guanqun , Cheng Chundong , Zhao Zhongjie , Zhang Tao , Li Le , Sun Bei
Published: July 2021

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease that typically features a dramatic desmoplastic reaction, especially fibroblasts. The roles of cancer-associated fibroblasts (CAFs) in PDAC have received more attention in recent years. As increasing evidence suggests the heterogeneity of CAFs in PDAC, different CAF subtypes have been shown to support tumor growth, while others suppress cancer proliferation. Myofibrotic CAFs (myCAFs) show alpha-smooth muscle actin (α-SMA)high interleukin-6 (IL-6)low myofibroblastic features, are activated by direct contact with tumor cells, and are located in the periglandular region. Inflammatory CAFs (iCAFs) show α-SMAlow IL-6high inflammatory features, are activated by paracrine factors secreted from tumor cells, and are located away from cancer cells. Antigen-presenting CAFs (apCAFs) show major histocompatibility complex II (MHC II) family genes that are highly expressed. CAFs have also been gradually explored as diagnostic and prognostic markers in pancreatic cancer. Targeted therapy of CAFs in PDAC has gradually attracted attention. With the deepening of related studies, some meaningful positive and negative results have surfaced, and CAFs may be the key to unlocking the door to pancreatic cancer treatment. Our review summarizes recent advances in the heterogeneity, function, and markers of CAFs in pancreatic cancer, as well as research and treatment targeting CAFs in pancreatic cancer.
Comparative Transcriptional Analysis of Pulmonary Arterial Hypertension Associated With Three Different Diseases
Authors: Wang Wei , Jiang Zhenhong , Zhang Dandan , Fu Linghua , Wan Rong , Hong Kui
Published: July 2021

Pulmonary arterial hypertension (PAH) is a severe cardiovascular disorder with high mortality. Multiple clinical diseases can induce PAH, but the underlying molecular mechanisms shared in PAHs associated with different diseases remain unclear. The aim of this study is to explore the key candidate genes and pathways in PAH associated with congenital heart disease (CHD-PAH), PAH associated with connective tissue disease (CTD-PAH), and idiopathic PAH (IPAH). We performed differential expression analysis based on a public microarray dataset GSE113439 and identified 1,442 differentially expressed genes, of which 80.3% were upregulated. Subsequently, both pathway enrichment analysis and protein–protein interaction network analysis revealed that the “Cell cycle” and “DNA damage” processes were significantly enriched in PAH. The expression of seven upregulated candidate genes (EIF2AK2, TOPBP1, CDC5L, DHX15, and CUL1–3) and three downregulated candidate genes (DLL4, EGFL7, and ACE) were validated by qRT-PCR. Furthermore, cell cycle-related genes Cul1 and Cul2 were identified in pulmonary arterial endothelial cells (PAECs) in vitro. The result revealed an increased expression of Cul2 in PAECs after hypoxic treatment. Silencing Cul2 could inhibit overproliferation and migration of PAECs in hypoxia. Taken together, according to bioinformatic analyses, our work revealed that “Cell cycle” and “DNA damage” process-related genes and pathways were significantly dysregulated expressed in PAHs associated with three different diseases. This commonality in molecular discovery might broaden the genetic perspective and understanding of PAH. Besides, silencing Cul2 showed a protective effect in PAECs in hypoxia. The results may provide new treatment targets in multiple diseases induced by PAH.
Hormone-Responsive BMP Signaling Expands Myoepithelial Cell Lineages and Prevents Alveolar Precocity in Mammary Gland
Authors: Shao Chunlei , Lou Pengbo , Liu Ruiqi , Bi Xueyun , Li Guilin , Yang Xu , Sheng Xiaole , Xu Jiuzhi , Lv Cong , Yu Zhengquan
Published: July 2021

Myoepithelial and luminal cells synergistically expand in the mammary gland during pregnancy, and this process is precisely governed by hormone-related signaling pathways. The bone morphogenetic protein (BMP) signaling pathway is now known to play crucial roles in all organ systems. However, the functions of BMP signaling in the mammary gland remain unclear. Here, we found that BMPR1a is upregulated by hormone-induced Sp1 at pregnancy. Using a doxycycline (Dox)-inducible BMPR1a conditional knockout mouse model, we demonstrated that loss of BMPR1a in myoepithelium results in compromised myoepithelial integrity, reduced mammary stem cells and precocious alveolar differentiation during pregnancy. Mechanistically, BMPR1a regulates the expression of p63 and Slug, two key regulators of myoepithelial maintenance, through pSmad1/5-Smad4 complexes, and consequently activate P-cadherin during pregnancy. Furthermore, we observed that loss of BMPR1a in myoepithelium results in the upregulation of a secreted protein Spp1 that could account for the precocious alveolar differentiation in luminal layer, suggesting a defective basal-to-luminal paracrine signaling mechanism. Collectively, these findings identify a novel role of BMP signaling in maintaining the identity of myoepithelial cells and suppressing precocious alveolar formation.
Hypoxia-Induced Mitogenic Factor: A Multifunctional Protein Involved in Health and Disease
Authors: Lv Moyang , Liu Wenjuan
Published: July 2021

Hypoxia-induced mitogenic factor (HIMF), also known as resistin-like molecule α (RELMα) or found in inflammatory zone 1 (FIZZ1) is a member of the RELM protein family expressed in mice. It is involved in a plethora of physiological processes, including mitogenesis, angiogenesis, inflammation, and vasoconstriction. HIMF expression can be stimulated under pathological conditions and this plays a critical role in pulmonary, cardiovascular and metabolic disorders. The present review summarizes the molecular characteristics, and the physiological and pathological roles of HIMF in normal and diseased conditions. The potential clinical significance of these findings for human is also discussed.
Developing C2-Aroyl Indoles as Novel Inhibitors of IDO1 and Understanding Their Mechanism of Inhibition via Mass Spectroscopy, QM/MM Calculations and Molecular Dynamics Simulation
Authors: Chauhan Jyoti , Maddi Srinivas R. , Dubey Kshatresh Dutta , Sen Subhabrata
Published: July 2021

Indoleamine-2,3-dioxygenase (IDO1) and tryptophan dioxygenases are two heme based metalloenzymes that catalyze the tryptophan oxidation reaction by inserting molecular dioxygen to cleave the pyrrole ring. The mechanism of such ring cleavage reaction is of carcinogenic importance as the malignant tumors recruit this mechanism for immune invasion. In the presence study, we have synthesized a Novel C2 aroyl indoles inhibitor, 8d, which shows significant inhibition of 180 nM at IC50 scale. The binding and conformational changes that transpire after inhibitor binding were thoroughly studied by molecular docking and MD simulations. The subsequent QM/MM (Quantum Mechanical/Molecular Mechanical) calculations were used to proposed the mechanism of inhibition. The QM/MM calculations show that the reaction proceeds via multistep processes where the dioxygen insertion to the substrate 8a is the rate determining process. Theoretical mechanism is further supported by mass spectroscopy, and drug metabolism/pharmacokinetics study (DMPK) and metabolic stability of compound 8d was investigated in rat and human liver microsomes.
Eimeria bovis Macromeront Formation Induces Glycolytic Responses and Mitochondrial Changes in Primary Host Endothelial Cells
Authors: Velásquez Zahady D. , López-Osorio Sara , Mazurek Sybille , Hermosilla Carlos , Taubert Anja
Published: July 2021

Eimeria bovis is an intracellular apicomplexan parasite that causes considerable economic losses in the cattle industry worldwide. During the first merogony, E. bovis forms large macromeronts with >140,000 merozoites I in host endothelial cells. Because this is a high-energy demanding process, E. bovis exploits the host cellular metabolism to fulfill its metabolic requirements. We here analyzed the carbohydrate-related energetic metabolism of E. bovis–infected primary bovine umbilical vein endothelial cells during first merogony and showed that during the infection, E. bovis–infected culture presented considerable changes in metabolic signatures, glycolytic, and mitochondrial responses. Thus, an increase in both oxygen consumption rates (OCR) and extracellular acidification rates (ECAR) were found in E. bovis–infected host cells indicating a shift from quiescent to energetic cell status. Enhanced levels of glucose and pyruvate consumption in addition to increased lactate production, suggesting an important role of glycolysis in E. bovis–infected culture from 12 days p.i. onward. This was also tested by glycolytic inhibitors (2-DG) treatment, which reduced the macromeront development and diminished merozoite I production. As an interesting finding, we observed that 2-DG treatment boosted sporozoite egress. Referring to mitochondrial activities, intracellular ROS production was increased toward the end of merogony, and mitochondrial potential was enhanced from 12 d p. i. onward in E. bovis–infected culture. Besides, morphological alterations of membrane potential signals also indicated mitochondrial dysfunction in macromeront-carrying host endothelial culture.
Scientific Literacy Linked to Attitudes Toward COVID-19 Vaccinations: A Pre-Registered Study
Authors: Motoki Kosuke , Saito Toshiki , Takano Yuji
Published: July 2021

The ongoing COVID-19 pandemic, which began in early 2020, is a global public health crisis. To prevent the spread of COVID-19, it is necessary to promote vaccine administration and preventive behaviors (e.g., mask, handwashing, social distancing). However, some people have negative attitudes toward vaccine administration and preventive behaviors. Based on the information-deficit model, the present study investigated how scientific literacy and perceived understanding of COVID-19 are associated with attitudes toward COVID-19 vaccinations and preventive behaviors. The findings demonstrated that both scientific literacy and perceived understanding of COVID-19 vaccines were positively associated with attitudes toward COVID-19 vaccines. Additionally, perceived understanding of COVID-19 preventive behaviors (but not scientific literacy) was positively associated with attitudes toward/practice of COVID-19 preventive behaviors. Collectively, our findings revealed the role of cognitive factors in preventing the global public health crisis and demonstrated the roles of objective and subjective knowledge on attitudes toward COVID-19 vaccinations and preventive behaviors.
Atrial Fibrillation and Cancer
Authors: Hajjar Ludhmila Abrahao , Fonseca Silvia Moulin Ribeiro , Machado Theuran Inahja Vicente
Published: July 2021

Cancer patients have a higher risk of atrial fibrillation (AF) than general population, the pathophysiology mechanisms involves the pro inflammatory status of immune system in these patients and the exacerbated inflammatory response to cancer treatment and surgeries. Adequate management and prophylaxis for its occurrence are important and reduce morbidity and mortality in this population. There is a challenge in AF related to cancer to predict thromboembolic and bleeding risk in these patients, once standard stroke and hemorrhagic prediction scores are not validated for them. It is used CHA2DS2-VASc and HAS-BLED scores, the same as used in general population. In this review, we demonstrate correlated mechanisms to occurrence AF in cancer patients as well as therapeutic challenges in this population.
Applying a Digital Health Checklist and Readability Tools to Improve Informed Consent for Digital Health Research
Authors: Nebeker Camille , Gholami Maryam , Kareem Daniah , Kim Emily
Published: July 2021

Background: As research involving human participants increasingly occurs with the aid of digital tools (e.g., mobile apps, wearable and remote pervasive sensors), the consent content and delivery process is changing. Informed consent documents to participate in research are lengthy and difficult for prospective participants to read and understand. As the consent communication will need to include concepts and procedures unique to digital health research, making that information accessible and meaningful to the prospective participant is critical for consent to be informed. This paper describes a methodology that researchers can apply when developing a consent communication for digital health research.

Methods: A consent document approved by a US institutional review board was deconstructed into segments that aligned with federal requirements for informed consent. Three researchers independently revised each segment of text with a goal of achieving a readability score between a 6–8th grade level. The team then consulted with an external readability expert well-versed in revising informed consent documents into “plain language.” The resulting text was evaluated using Microsoft Word and Online-Utility accessibility software. The final step involved adding visual images and graphics to complement the text. The Digital Health Checklist consent prototype builder was then used to identify areas where the consent content could be expanded to address four key domains of Access and Usability, Privacy, Risks and Benefits, and Data Management.

Results: The approved consent was evaluated at a 12.6 grade reading level, whereas the revised language by our study team received 12.4, 12, and 12.58, respectively. The final consent document synthesized the most readable of the three revised versions and was further revised to include language recommended by the software tool for improving readability, which resulted in a final revised consent readability score of a 9.2 grade level. Moreover, word count was reduced from 6,424 in the original consent to 679 in the rewritten consent form.

Conclusion: Utilizing an iterative process to design an accessible informed consent document is a first step in achieving meaningful consent to participate in digital health research. This paper describes how a consent form approved by an institutional review board can be made more accessible to a prospective research participant by improving the document readability score, reducing the word count and assessing alignment with the Digital Health Checklist.
Calcium Ionophore (A23187) Rescues the Activation of Unfertilized Oocytes After Intracytoplasmic Sperm Injection and Chromosome Analysis of Blastocyst After Activation
Authors: Xu Ziwen , Yao Guidong , Niu Wenbin , Fan Huiying , Ma Xueshan , Shi Senlin , Jin Haixia , Song Wenyan , Sun Yingpu
Published: July 2021

Calcium is a crucial factor in regulating the biological behavior of cells. The imbalance of calcium homeostasis in cytoplasm will cause abnormal behavior of cells and the occurrence of diseases. In intracytoplasmic sperm injection (ICSI) cycle, the dysfunction of oocyte activation caused by insufficient release of Ca2+ from endoplasmic reticulum is one of the main reasons for repeated fertilization failure. Calcium ionophore (A23187) is a highly selective calcium ionophore, which can form stable complex with Ca2+ and pass through the cell membrane at will, effectively increasing intracellular Ca2+ levels. It has been reported that calcium ionophore (A23187) can activate oocytes and obtain normal embryos. However, there are few studies on unfertilized oocytes after calcium ionophore (A23187) rescue activation in ICSI cycle. The purpose of this study was to analyze the effects of calcium ionophore (A23187) rescue activation on the activation of unfertilized oocytes, embryonic development potential, embryonic development timing and chromosomal aneuploidy, and to compare and analyze the clinical data of patients with calcium ionophore (A23187) activation in clinical application. The results showed that a certain proportion of high-quality blastocysts with normal karyotype could be obtained after calcium ionophore (A23187) rescue activation of unfertilized oocytes, and it did not have a significant effect on the timing of embryo development. In clinical practice, direct activation with calcium ionophore (A23187) after ICSI was better than rescue activation the next day. In conclusions, the studies on the effectiveness and safety of calcium ionophore (A23187) rescue activation for oocytes with ICSI fertilization failure can enable some patients to obtain usable, high-quality embryos during the first ICSI cycle.
Self-Assembling Metabolon Enables the Cell Free Conversion of Glycerol to 1,3-Propanediol
Authors: Xu Qi , Alahuhta Markus , Hewitt Patrick , Sarai Nicholas S. , Wei Hui , Hengge Neal N. , Mittal Ashutosh , Himmel Michael E. , Bomble Yannick J.
Published: July 2021

Cell free biocatalysis is showing promise as a replacement or complement to conventional microbial biocatalysts due to the potential for achieving high yields, titers, and productivities. However, there exist several challenges that need to be addressed before its broader industrial adoption is achieved. New paradigms and innovative solutions are needed to overcome these challenges. In this study we demonstrate high levels of glycerol conversion to 1,3-propanediol using a self-assembling metabolic pathway leveraging the arraying strategy (protein scaffolds) used by thermophilic cellulolytic bacteria to assemble their biomass degrading enzymes. These synthetic metabolons were capable of producing 1,3-PDO at a yield more than 95% at lower glycerol concentration and close to 70% at higher concentrations at a higher productivity rate than the equivalent microbial strain. One of the benefits of our approach is the fact that no enzyme purification is required, and that the assembly of the complex is accomplished in vivo before immobilization, while product formation is conducted in vitro. We also report the recovery of enzymatic activity upon fusion enzymes binding to these protein scaffolds, which could have broader applications when assembling arrayed protein complexes.
A Systematic Review of Small Domain Estimation Research in Forestry During the Twenty-First Century From Outside the United States
Authors: Guldin Richard W.
Published: July 2021

Small domain estimation (SDE) research outside of the United States has been centered in Canada and Europe—both in transnational organizations, such as the European Union, and in the national statistics offices of individual countries. Support for SDE research is driven by government policy-makers responsible for core national statistics across domains. Examples include demographic information about provision of health care or education (a social domain) or business data for a manufacturing sector (economic domain). Small area estimation (SAE) research on forest statistics has typically studied a subset of core environmental statistics for a limited geographic domain. The statistical design and sampling intensity of national forest inventories (NFIs) provide population estimates of acceptable precision at the national level and sometimes for broad sub-national regions. But forest managers responsible for smaller areas—states/provinces, districts, counties—are facing changing market conditions, such as emerging forest carbon markets, and budgetary pressures that limit local forest inventories. They need better estimates of conditions and trends for small sub-sets of a national-scale domain than can be provided at acceptable levels of precision from NFIs. Small area estimation research is how forest biometricians at the science-policy interface build bridges to inform decisions by forest managers, landowners, and investors.
NOTCH3 Variants and Genotype-Phenotype Features in Chinese CADASIL Patients
Authors: Hu Yacen , Sun Qiying , Zhou Yafang , Yi Fang , Tang Haiyun , Yao Lingyan , Tian Yun , Xie Nina , Luo Mengchuan , Wang Zhiqin , Liao Xinxin , Xu Hongwei , Zhou Lin
Published: July 2021

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a cerebral small vessel disease caused by mutations in the NOTCH3 gene. Archetypal disease-causing mutations are cysteine-affecting variants within the 34 epidermal growth factor-like repeat (EGFr) region of the Notch3 extracellular subunit. Cysteine-sparing variants and variants outside the EGFr coding region associated with CADASIL phenotype have been reported. However, the linkage between untypical variants and CADASIL is unclear. In this study, we investigated the spectrum of NOTCH3 variants in a cohort of 38 probands from unrelated families diagnosed as CADASIL. All coding exons of the NOTCH3 gene were analyzed, and clinical data were retrospectively studied. We identified 23 different NOTCH3 variants including 14 cysteine-affecting pathogenic variants, five cysteine-sparing pathogenic variants, two reported cysteine-sparing variants of unknown significance (VUS), and two novel VUS outside EGFr region. In retrospective studies of clinical data, we found that patients carrying cysteine-sparing pathogenic variants showed later symptom onset (51.36 ± 7.06 vs. 44.96 ± 8.82, p = 0.023) and milder temporal lobe involvement (1.50 ± 1.74 vs. 3.11 ± 2.32, p = 0.027) than patients carrying cysteine-affecting pathogenic variants. Our findings suggested that untypical variants comprise a significant part of NOTCH3 variants and may be associated with a distinctive phenotype.
DNA Damage Repair Status Predicts Opposite Clinical Prognosis Immunotherapy and Non-Immunotherapy in Hepatocellular Carcinoma
Authors: Chen Yunfei , Wang Xu , Deng Xiaofan , Zhang Yu , Liao Rui , Li Youzan , Yang Hongji , Chen Kai
Published: July 2021

Immune checkpoint inhibitors(ICIs) that activate tumor-specific immune responses bring new hope for the treatment of hepatocellular carcinoma(HCC). However, there are still some problems, such as uncertain curative effects and low objective response rates, which limit the curative effect of immunotherapy. Therefore, it is an urgent problem to guide the use of ICIs in HCC based on molecular typing. We downloaded the The Cancer Genome Atlas-Liver hepatocellular carcinoma(TCGA-LIHC) and Mongolian-LIHC cohort. Unsupervised clustering was applied to the highly variable data regarding expression of DNA damage repair(DDR). The CIBERSORT was used to evaluate the proportions of immune cells. The connectivity map(CMap) and pRRophetic algorithms were used to predict the drug sensitivity. There were significant differences in DDR molecular subclasses in HCC(DDR1 and DDR2), and DDR1 patients had low expression of DDR-related genes, while DDR2 patients had high expression of DDR-related genes. Of the patients who received traditional treatment, DDR2 patients had significantly worse overall survival(OS) than DDR1 patients. In contrast, of the patients who received ICIs, DDR2 patients had significantly prolonged OS compared with DDR1 patients. Of the patients who received traditional treatment, patients with high DDR scores had worse OS than those with low DDR scores. However, the survival of patients with high DDR scores after receiving ICIs was significantly higher than that of patients with low DDR scores. The DDR scores of patients in the DDR2 group were significantly higher than those of patients in the DDR1 group. The tumor microenvironment(TME) of DDR2 patients was highly infiltrated by activated immune cells, immune checkpoint molecules and proinflammatory molecules and antigen presentation-related molecules. In this study, HCC patients were divided into the DDR1 and DDR2 group. Moreover, DDR status may serve as a potential biomarker to predict opposite clinical prognosis immunotherapy and non-immunotherapy in HCC.
The Role of Cysteine Peptidases in Hematopoietic Stem Cell Differentiation and Modulation of Immune System Function
Authors: Perišić Nanut Milica , Pečar Fonović Urša , Jakoš Tanja , Kos Janko
Published: July 2021

Cysteine cathepsins are primarily involved in the degradation and recycling of proteins in endo-lysosomal compartments but are also gaining recognition as pivotal proteolytic contributors to various immune functions. Through their extracellular proteolytic activities within the hematopoietic stem cell niche, they are involved in progenitor cell mobilization and differentiation. Cysteine cathepsins, such as cathepsins L and S contribute to antigen-induced adaptive immunity through major histocompatibility complex class II antigen presentation whereas cathepsin X regulates T-cell migration. By regulating toll-like receptor signaling and cytokine secretion cysteine cathepsins activate innate immune cells and affect their functional differentiation. Cathepsins C and H are expressed in cytotoxic T lymphocytes and natural killer cells and are involved in processing of pro-granzymes into proteolytically active forms. Cytoplasmic activities of cathepsins B and L contribute to the maintenance of homeostasis of the adaptive immune response by regulating cell death of T and B lymphocytes. The expression pattern, localization, and activity of cysteine cathepsins is tightly connected to their function in immune cells. Furthermore, cysteine cathepsins together with their endogenous inhibitors, serve as mediators in the interplay between cancer and immune cells that results in immune cell anergy. The aim of the present article is to review the mechanisms of dysregulation of cysteine cathepsins and their inhibitors in relation to immune dysfunction to address new possibilities for regulation of their function.
Mechanosensation and Mechanotransduction in Natural Killer Cells
Authors: Santoni Giorgio , Amantini Consuelo , Santoni Matteo , Maggi Federica , Morelli Maria Beatrice , Santoni Angela
Published: July 2021

Natural killer (NK) cells are a main subset of innate lymphocytes that contribute to host immune protection against viruses and tumors by mediating target cell killing and secreting a wide array of cytokines. Their functions are finely regulated by a balance between activating and inhibitory receptors and involve also adhesive interactions. Mechanotransduction is the process in which physical forces sensed by mechanosensors are translated into chemical signaling. Herein, we report findings on the involvement of this mechanism that is mainly mediated by actin cytoskeleton, in the regulation of NK cell adhesion, migration, tissue infiltration and functions. Actin represents the structural basis for NK cell immunological synapse (NKIS) and polarization of secretory apparatus. NK-target cell interaction involves the formation of both uropods and membrane nanotubes that allow target cell interaction over long distances. Actin retrograde flow (ARF) regulates NK cell signaling and controls the equilibrium between activationversusinhibition. Activating NKIS is associated with rapid lamellipodial ARF, whereas lower centripetal actin flow is present during inhibitory NKIS where β actin can associate with the tyrosine phosphatase SHP-1. Overall, a better knowledge of mechanotransduction might represent a future challenge: Realization of nanomaterials tailored for NK cells, would be important to translatein vitrostudies inin vivonew immunotherapeutic approaches.
Ancient DNA Study in Medieval Europeans Shows an Association Between HLA-DRB1*03 and Paratyphoid Fever
Authors: Haller Magdalena , Bonczarowska Joanna H. , Rieger Dirk , Lenz Tobias L. , Nebel Almut , Krause-Kyora Ben
Published: July 2021

Outbreaks of infectious diseases repeatedly affected medieval Europe, leaving behind a large number of dead often inhumed in mass graves. Human remains interred in two burial pits from 14th century CE Germany exhibited molecular evidence of Salmonella enterica Paratyphi C (S. Paratyphi C) infection. The pathogen is responsible for paratyphoid fever, which was likely the cause of death for the buried individuals. This finding presented the unique opportunity to conduct a paratyphoid fever association study in a European population. We focused on HLA-DRB1*03:01 that is a known risk allele for enteric fever in present-day South Asians. We generated HLA profiles for 29 medieval S. Paratyphi C cases and 24 contemporaneous controls and compared these to a modern German population. The frequency of the risk allele was higher in the medieval cases (29.6%) compared to the contemporaneous controls (13%; p = 0.189), albeit not significantly so, possibly because of small sample sizes. Indeed, in comparison with the modern controls (n = 39,689; 10.2%; p = 0.005) the frequency difference became statistically significant. This comparison also suggested a slight decrease in the allele’s prevalence between the medieval and modern controls. Up to now, this is the first study on the genetic predisposition to Salmonella infection in Europeans and the only association analysis on paratyphoid fever C. Functional investigation using computational binding prediction between HLA variants and S. Paratyphi and S. Typhi peptides supported a reduced recognition capacity of bacterial proteins by DRB1*03:01 relative to other common DRB1 variants. This pattern could potentially explain the disease association. Our results suggest a slightly reduced predisposition to paratyphoid fever in modern Europeans. The causative allele, however, is still common today, which can be explained by a trade-off, as DRB1*03:01 is protective against infectious respiratory diseases such as severe respiratory syndrome (SARS). It is thus possible that the allele also provided resistance to corona-like viruses in the past.
Inhibitory Molecules PD-1, CD73 and CD39 Are Expressed by CD8+ T Cells in a Tissue-Dependent Manner and Can Inhibit T Cell Responses to Stimulation
Authors: Smith Corinne J. , Snyder Christopher M.
Published: July 2021

The salivary gland is an important tissue for persistence and transmission of multiple viruses. Previous work showed that salivary gland tissue-resident CD8+ T cells elicited by viruses were poorly functional ex vivo. Using a model of persistent murine cytomegalovirus (MCMV) infection, we now show that CD8+ T cells in the salivary gland and other non-lymphoid tissues of mice express multiple molecules associated with T cell exhaustion including PD-1, CD73 and CD39. Strikingly however, these molecules were expressed independently of virus or antigen. Rather, PD-1-expressing T cells remained PD-1+ after migration into tissues regardless of infection, while CD73 was activated on CD8+ T cells by TGF-β signaling. Blockade of PD-L1, but not CD73, improved cytokine production by salivary gland T cells ex vivo and increased the expression of granzyme B after stimulation within the salivary gland. Nevertheless, salivary-gland localized CD8+ T cells could kill PD-L1-expressing targets in vivo, albeit with modest efficiency, and this was not improved by PD-L1 blockade. Moreover, the impact of PD-L1 blockade on granzyme B expression waned with time. In contrast, the function of kidney-localized T cells was improved by CD73 blockade, but was unaffected by PD-L1 blockade. These data show that tissue localization per se is associated with expression of inhibitory molecules that can impact T cell function, but that the functional impact of this expression is context- and tissue-dependent.
Marine Organisms as a Rich Source of Biologically Active Peptides
Authors: Macedo Maria Wanna Figueiredo Sena , Cunha Nicolau Brito da , Carneiro Juliana Araújo , Costa Rosiane Andrade da , Alencar Sergio Amorim de , Cardoso Marlon Henrique , Franco Octávio Luiz , Dias Simoni Campos
Published: July 2021

Oceanic environments are one of the largest sources of bioactive molecules, due to the high degree of biodiversity and the innumerable ecological relationships established between macro and microorganisms found in the different ecosystems of these complex environments. Marine organisms are being studied increasingly because they are considered important producers of biologically active peptides. Peptides extracted from marine sources have different functions and structures, when compared to peptides isolated from terrestrial sources, considering the different adaptive pressures undergone by these organisms throughout the evolutionary process. Most bioactive compounds isolated from marine environments are obtained from symbiont microorganisms. Of these microorganisms, bacteria are an important source of bioactive peptides, isolated by metagenomic studies from complex gene networks expressed under marine conditions. Several peptides have been shown to have biotechnological properties such as antimicrobial, antitumor, antihypertensive, anticoagulant, anti-fouling, and antioxidant activity and can be used in the pharmaceutical and food industries. This review article aims to provide an overview of peptides of biotechnological importance, isolated from different phyla of marine organisms, examining the relationship between structure and function of some of these peptides, as well as the ways of extracting, purifying and prospecting new peptides by traditional methods of isolation or sequence analysis in databases. It also intends to list the peptides that are already being produced and used by the industry, in its various branches, and their current state in the market and in clinical tests.
A Novel RNA-Binding Protein Signature to Predict Clinical Outcomes and Guide Clinical Therapy in Gastric Cancer
Authors: Qiu Zhigang , Jiang Haitao , Ju Kun , Liu Xichun
Published: July 2021

Objective: This study aimed to develop an RNA-binding protein (RBP)-based signature for risk stratification and guiding clinical therapy in gastric cancer.

Methods: Based on survival-related RBPs, an RBP-based signature was established by LASSO regression analysis in TCGA dataset. Kaplan–Meier curves were drawn between high- and low-risk groups. The predictive efficacy of this signature was assessed via ROCs at 1-, 3-, and 5-year survival. Its generalizability was verified in an external dataset. Following adjustment with other clinicopathological characteristics, the independency of survival prediction was evaluated via multivariate Cox regression and subgroup analyses. GSEA was utilized in identifying activated pathways in two groups. Stromal score, immune score, tumor purity, and infiltration levels of 22 immune cells were determined in each sample via the ESTIMATE and CIBERSORT algorithms. The sensitivity to chemotherapy drugs was assessed through the GDSC database.

Results: Data showed that patients with high risk exhibited unfavorable clinical outcomes than those with low risk. This signature possessed good performance in predicting 1-, 3-, and 5-year survival and can be independently predictive of patients' survival. Calcium, ECM receptor interaction, and focal adhesion were highly enriched in high-risk samples. High-risk samples presented increased stromal and immune scores and reduced tumor purity. Moreover, this signature presented close relationships with immune infiltrations. Low-risk specimens were more sensitive to sorafenib, gefitinib, vinorelbine, and gemcitabine than high-risk specimens.

Conclusion: This RBP-based signature may be a promising tool for predicting clinical outcomes and guiding clinical therapy in gastric cancer.
A Nomogram-Based Risk Classification System Predicting the Overall Survival of Patients With Newly Diagnosed Stage IVB Cervix Uteri Carcinoma
Authors: Yu Wenke , Huang Lu , Zhong Zixing , Song Tao , Xu Hong'en , Jia Yongshi , Hu Jinming , Shou Huafeng
Published: July 2021

Background: This study constructed and demonstrated a model to predict the overall survival (OS) of newly diagnosed distant metastatic cervical cancer (mCC) patients.

Methods: The SEER (Surveillance, Epidemiology, and End Results) database was used to collect the eligible data, which from 2010 to 2016. Then these data were separated into training and validation cohorts (7:3) randomly. Cox regression analyses was used to identify parameters significantly correlated with OS. Harrell's Concordance index (C-index), calibration curves, and decision curve analysis (DCA) were further applied to verify the performance of this model.

Results: A total of 2,091 eligible patients were enrolled and randomly split into training (n = 1,467) and validation (n = 624) cohorts. Multivariate analyses revealed that age, histology, T stage, tumor size, metastatic sites, local surgery, chemotherapy, and radiotherapy were independent prognostic parameters and were then used to build a nomogram for predicting 1 and 2-year OS. The C-index of training group and validation group was 0.714 and 0.707, respectively. The calibration curve demonstrated that the actual observation was in good agreement with the predicted results concluded by the nomogram model. Its clinical usefulness was further revealed by the DCAs. Based on the scores from the nomogram, a corresponding risk classification system was constructed. In the overall population, the median OS time was 23.0 months (95% confidence interval [CI], 20.5–25.5), 12.0 months (95% CI, 11.1–12.9), and 5.0 months (95% CI, 4.4–5.6), in the low-risk group, intermediate-risk group, and high-risk group, respectively.

Conclusion: A novel nomogram and a risk classification system were established in this study, which purposed to predict the OS time with mCC patients. These tools could be applied to prognostic analysis and should be validated in future studies.
Gene Validation and Remodelling Using Proteogenomics of Phytophthora cinnamomi, the Causal Agent of Dieback
Authors: Andronis Christina E. , Hane James K. , Bringans Scott , Hardy Giles E. S. J. , Jacques Silke , Lipscombe Richard , Tan Kar-Chun
Published: July 2021

Phytophthora cinnamomi is a pathogenic oomycete that causes plant dieback disease across a range of natural ecosystems and in many agriculturally important crops on a global scale. An annotated draft genome sequence is publicly available (JGI Mycocosm) and suggests 26,131 gene models. In this study, soluble mycelial, extracellular (secretome), and zoospore proteins of P. cinnamomi were exploited to refine the genome by correcting gene annotations and discovering novel genes. By implementing the diverse set of sub-proteomes into a generated proteogenomics pipeline, we were able to improve the P. cinnamomi genome annotation. Liquid chromatography mass spectrometry was used to obtain high confidence peptides with spectral matching to both the annotated genome and a generated 6-frame translation. Two thousand seven hundred sixty-four annotations from the draft genome were confirmed by spectral matching. Using a proteogenomic pipeline, mass spectra were used to edit the P. cinnamomi genome and allowed identification of 23 new gene models and 60 edited gene features using high confidence peptides obtained by mass spectrometry, suggesting a rate of incorrect annotations of 3% of the detectable proteome. The novel features were further validated by total peptide support, alongside functional analysis including the use of Gene Ontology and functional domain identification. We demonstrated the use of spectral data in combination with our proteogenomics pipeline can be used to improve the genome annotation of important plant diseases and identify missed genes. This study presents the first use of spectral data to edit and manually annotate an oomycete pathogen.
Identification of a Human Anti-Alpha-Toxin Monoclonal Antibody Against Staphylococcus aureus Infection
Authors: Liu Fangjie , Guan Zhangchun , Liu Yu , Li Jingjing , Liu Chenghua , Gao Yaping , Ma Yuanfang , Feng Jiannan , Shen Beifen , Yang Guang
Published: July 2021

Staphylococcus aureus is a major pathogenic bacterium that causes a variety of clinical infections. The emergence of multi-drug resistant mechanisms requires novel strategies to mitigate S. aureus infection. Alpha-hemolysin (Hla) is a key virulence factor that is believed to play a significant role in the pathogenesis of S. aureus infections. In this study, we screened a naïve human Fab library for identification of monoclonal antibodies targeting Hla by phage display technology. We found that the monoclonal antibody YG1 blocked the Hla-mediated lysis of rabbit red blood cells and inhibited Hla binding to A549 cells in a concentration-dependent manner. YG1 also provided protection against acute peritoneal infection, bacteremia, and pneumonia in murine models. We further characterized its epitope using different Hla variants and found that the amino acids N209 and F210 of Hla were functionally and structurally important for YG1 binding. Overall, these results indicated that targeting Hla with YG1 could serve as a promising protective strategy against S. aureus infection.
When the Going Gets Rough: The Significance of Brucella Lipopolysaccharide Phenotype in Host–Pathogen Interactions
Authors: Stranahan Lauren W. , Arenas-Gamboa Angela M.
Published: July 2021

Brucellais a facultatively intracellular bacterial pathogen and the cause of worldwide zoonotic infections, infamous for its ability to evade the immune system and persist chronically within host cells. Despite the frequent association with attenuation in other Gram-negative bacteria, a rough lipopolysaccharide phenotype is retained byBrucella canisandBrucella ovis, which remain fully virulent in their natural canine and ovine hosts, respectively. While these natural rough strains lack the O-polysaccharide they, like their smooth counterparts, are able to evade and manipulate the host immune system by exhibiting low endotoxic activity, resisting destruction by complement and antimicrobial peptides, entering and trafficking within host cells along a similar pathway, and interfering with MHC-II antigen presentation.B. canisandB. ovisappear to have compensated for their roughness by alterations to their outer membrane, especially in regards to outer membrane proteins.B. canis, in particular, also shows evidence of being less proinflammatoryin vivo, suggesting that the rough phenotype may be associated with an enhanced level of stealth that could allow these pathogens to persist for longer periods of time undetected. Nevertheless, much additional work is required to understand the correlates of immune protection against the natural roughBrucellaspp., a critical step toward development of much-needed vaccines. This review will highlight the significance of rough lipopolysaccharide in the context of both natural disease and host–pathogen interactions with an emphasis on natural roughBrucellaspp. and the implications for vaccine development.