bluuebunny/crossref_metadata_2025 huggingface dataset:
Development and Initial Validation of the Confidence and Motivation to Teach Primary Physical Education Questionnaire
Authors: Spittle Sharna , Watt Anthony P. , Spittle Michael
Published: May 2022

This research describes the development and psychometric evaluation of the Confidence and Motivation to Teach Primary Physical Education Questionnaire (CMTPPEQ). Phase 1 involved questionnaire development and quantitative analysis of reliability and use of exploratory factor analysis (EFA) to examine factor structure and validity with 161 pre-service teachers. The EFA revealed two confidence factors and five motivation factors. All factors displayed adequate internal consistency and acceptable test-retest reliability for the confidence factors and three motivation factors. In Phase 2, the measure was further evaluated and factor structure refined using confirmatory factor analysis (CFA), with 211 pre-service and 107 in-service teachers. The two-factor confidence structure of Management and Planning and Implementation was confirmed with acceptable levels of fit. Structural changes made to the motivation structure resulted in six factors: Knowledge, Practice, Introjected Performance, Professional Expectations, Student Outcomes, and Disengagement. All factors demonstrated adequate internal consistency.
Potential of Endogenous Oxytocin in Endocrine Treatment and Prevention of COVID-19
Authors: Wang Stephani C. , Zhang Fengmin , Zhu Hui , Yang Haipeng , Liu Yang , Wang Ping , Parpura Vladimir , Wang Yu-Feng
Published: May 2022

Coronavirus disease 2019 or COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a significant threat to the health of human beings. While wearing mask, maintaining social distance and performing self-quarantine can reduce virus spreading passively, vaccination actively enhances immune defense against COVID-19. However, mutations of SARS-CoV-2 and presence of asymptomatic carriers frustrate the effort of completely conquering COVID-19. A strategy that can reduce the susceptibility and thus prevent COVID-19 while blocking viral invasion and pathogenesis independent of viral antigen stability is highly desirable. In the pathogenesis of COVID-19, endocrine disorders have been implicated. Correspondingly, many hormones have been identified to possess therapeutic potential of treating COVID-19, such as estrogen, melatonin, corticosteroids, thyroid hormone and oxytocin. Among them, oxytocin has the potential of both treatment and prevention of COVID-19. This is based on oxytocin promotion of immune-metabolic homeostasis, suppression of inflammation and pre-existing comorbidities, acceleration of damage repair, and reduction of individuals’ susceptibility to pathogen infection. Oxytocin may specifically inactivate SARS-COV-2 spike protein and block viral entry into cellsviaangiotensin-converting enzyme 2 by suppressing serine protease and increasing interferon levels and number of T-lymphocytes. In addition, oxytocin can promote parasympathetic outflow and the secretion of body fluids that could dilute and even inactivate SARS-CoV-2 on the surface of cornea, oral cavity and gastrointestinal tract. What we need to do now is clinical trials. Such trials should fully balance the advantages and disadvantages of oxytocin application, consider the time- and dose-dependency of oxytocin effects, optimize the dosage form and administration approach, combine oxytocin with inhibitors of SARS-CoV-2 replication, apply specific passive immunization, and timely utilize efficient vaccines. Meanwhile, blocking COVID-19 transmission chain and developing other efficient anti-SARS-CoV-2 drugs are also important. In addition, relative to the complex issues with drug applications over a long term, oxytocin can be mobilized through many physiological stimuli, and thus used as a general prevention measure. In this review, we explore the potential of oxytocin for treatment and prevention of COVID-19 and perhaps other similar pathogens.
Weight Cycling and Dieting Behavior in Fitness Club Members
Authors: Haakstad Lene A. H. , Stensrud Trine , Rugseth Gro , Gjestvang Christina
Published: May 2022

Background

Along with the rising prevalence of high body-mass index (BMI), there is also increased emphasis on leanness and fitness. Both these trends suggest that many individuals are concerned about weight management and may try to lose weight. Using data from the research project “Fitness clubs - a venue for public health?”, we aimed to describe weight cycling and energy-restricted dieting in men and women at start-up of fitness club membership, and to investigate influencing factors [age, BMI, educational level, self-classified overweight/obesity, compliance with nutritional guidelines, unhealthy weight control strategies and self-perceived health (SPH)].

Methods

In a cross-sectional online survey, 250 men and women from 25 fitness clubs in Oslo, reported anthropometrics, self-classified weight group, weight cycling, weight loss/gain, eating habits/dieting, and background/health information. Enrollment was limited to adult (≥18 years) novice exercisers (exercising <60 min/week at a moderate or vigorous intensity or brisk walking <150 min/week, the past six months) with less than four weeks of membership. Factors associated with weight cycling were examined using simple and multiple logistic regression, separated for men and women.

Results

In both sexes (mean age: 36.4 ± 11.3, range 18-71 years), a high number reported substantial weight fluctuation (+/-5 kg) the past 12 months (men: 50% and women: 62%, mean difference 12%, 95% CI -0.3 to 23.8, p=0.056) and unhealthy weight control strategies (men: 24.8% and women: 47.2%, mean difference 22.4%, 95% CI 10.5 to 33.4, p<0.001). Weight cyclers had a higher mean BMI compared with non-cyclers (mean difference -1.5, 95% CI -2.6 to - 0.4, p= 0.003). Further, the difference in body weight was 6.7 kg (95% CI 2.2 to 10.8, p=0.004) and 10.8 kg (95% CI 5.8 to 15.8, <0.001) in men and women, respectively. Besides BMI status, self-classified overweight/obesity was the strongest predictor of reporting weight cycling (men: OR 5.54, 95% CI 2.03 to 15.12, p<0.01 and women: OR 7.17, 95% CI 2.48 to 20.68, p<0.001).

Conclusion

In novice exercisers, a large proportion reported weight cycling and unhealthy weight control strategies, and both were more prevalent in women than in men. Self-classified overweight was found to be the most important factor influencing weight cycling.
Physical Activity and Diet in a Global Pandemic: An Investigation of the Impact of COVID-19 on Factors Relevant for Musculoskeletal Health at Two Different Stages of the Lifecourse
Authors: Bevilacqua Gregorio , D’Angelo Stefania , Linaker Cathy , Paul Alice , Bloom Ilse , Zhang Jean , Laskou Faidra , Cooper Cyrus , Ward Kate A. , Walker-Bone Karen , Dennison Elaine M.
Published: May 2022

Background

Physical activity, nutrition and other lifestyle factors play important roles in maintaining musculoskeletal health. The coronavirus disease (COVID-19) originated in late 2019, spread globally to be declared a pandemic by the World Health Organisation in March 2020, and led to widespread behaviour change. The aim of this study was to use two existing cohorts, the Hertfordshire Cohort Study (HCS) and Health and Employment After Fifty Study (HEAF), to understand how wave one of the COVID-19 pandemic impacted lifestyle factors associated with musculoskeletal health in the UK.

Methods

125 eligible participants, 65 males and 60 females (drawn from the HCS study, median (IQR) age 84.3 (82.4-86.6) years, all Caucasian, and community dwelling) were contacted by telephone and asked to complete a questionnaire administered by a trained researcher. Data collection occurred over the period July 2020 to February 2021. 2469 participants, 1086 men and 1383 women (drawn from the HEAF study, median age 65.7 (62.0-69.3) years, mostly Caucasian and community dwelling) completed an online questionnaire in March 2021.

Results

In HCS, 47% respondents reported being less physically active than before the pandemic (and only 5% more so), 27% said they consumed less alcohol compared to pre-pandemic times (and only 3% more so), and 18% reported eating less than before, although quality of diet was generally unchanged over this timeframe surveyed. In HEAF, 44% participants said they were less active than before the pandemic, while 17% reported being more active. The majority of participants reported no changes in alcohol consumption and diet; however, 19% said they drank more than before (32% of which was above recommended levels), 16% said their diet was less healthy, and 19% reported eating more than before.

Conclusion

We have reported the experience of the first wave of the COVID-19 pandemic among participants of two Caucasian community dwelling UK cohorts, highlighting the impact of the pandemic on lifestyle factors associated with musculoskeletal health. Changed physical activity levels were reported in a high proportion of respondents in both studies; an investigation of reversibility of these changes is required.
Transformation of Resource-Based Cities: The Case of Benxi
Authors: Wang Xintong , Liu Hanbin , Chen Zhujun
Published: May 2022

Resource-based cities, which emerge due to the large-scale industrialization of China, mainly rely on local natural resources for industrial layout and economic development. However, resources have been gradually exhausted due to overuse, resulting in a series of negative impacts on the environment and resources. In order to realize long-term sustainable development and avoid falling into the “resource curse,” measures such as industrial structure adjustment and technological upgrading to promote the transformation of these cities ought to be implemented. Taking Benxi, one of the most typical mineral resource-based cities in China, as an example, this study discusses the economic and environmental performance and existing problems in the local transformation process, comparing it with successful transformation patterns of global mineral resource-based cities. On this basis, a series of policy suggestions together with possible ways toward sustainable development are put forward and summarized.
Single Nucleotide Polymorphism Effects on Lamb Fecal Egg Count Estimated Breeding Values in Progeny-Tested Katahdin Sires
Authors: Notter David R. , Heidaritabar Marzieh , Burke Joan M. , Shirali Masoud , Murdoch Brenda M. , Morgan James L. M. , Morota Gota , Sonstegard Tad S. , Becker Gabrielle M. , Spangler Gordon L. , MacNeil Michael D. , Miller James E.
Published: May 2022

Estimated breeding values (EBV) for fecal egg counts (FEC) at 42–90 days of age (WFEC) and 91–150 days of age (PFEC) for 84 progeny-tested Katahdin sires were used to identify associations of deregressed EBV with single-nucleotide polymorphisms (SNP) using 388,000 SNP with minor-allele frequencies ≥0.10 on an Illumina high-density ovine array. Associations between markers and FEC EBV were initially quantified by single-SNP linear regression. Effects of linkage disequilibrium (LD) were minimized by assigning SNP to 2,535 consecutive 1-Mb bins and focusing on the effect of the most significant SNP in each bin. Bonferroni correction was used to define bin-based (BB) genome- and chromosome-wide significance. Six bins on chromosome 5 achieved BB genome-wide significance for PFEC EBV, and three of those SNP achieved chromosome-wide significance after Bonferroni correction based on the 14,530 total SNP on chromosome 5. These bins were nested within 12 consecutive bins between 59 and 71 Mb on chromosome 5 that reached BB chromosome-wide significance. The largest SNP effects were at 63, 67, and 70 Mb, with LD among these SNP of r2 ≤ 0.2. Regional heritability mapping (RHM) was then used to evaluate the ability of different genomic regions to account for additive variance in FEC EBV. Chromosome-level RHM indicated that one 500-SNP window between 65.9 and 69.9 Mb accounted for significant variation in PFEC EBV. Five additional 500-SNP windows between 59.3 and 71.6 Mb reached suggestive (p < 0.10) significance for PFEC EBV. Although previous studies rarely identified markers for parasite resistance on chromosome 5, the IL12B gene at 68.5 Mb codes for the p40 subunit of both interleukins 12 and 23. Other immunoregulatory genes are also located in this region of chromosome 5, providing opportunity for additive or associative effects.
What’s Shape Got to Do With It? Examining the Relationship Between Facial Shape and Orofacial Clefting
Authors: Weinberg Seth M.
Published: May 2022

Nonsyndromic orofacial clefts belong to a class of congenital malformations characterized by a complex and multifactorial etiology. During early facial development, multiple factors can disrupt fusion leading to a cleft; this includes the shape of the embryonic face. The face shape hypothesis (FSH) of orofacial clefting emerged in the 1960s, influenced by morphological differences observed within affected families, comparative studies of mouse models, and advances in modeling genetic liability for complex traits in populations. For the past five decades, studies have documented changes in the shape or spatial arrangement of facial prominences in embryonic mice and altered post-natal facial shape in individuals at elevated risk for orofacial clefting due to their family history. Moreover, recent studies showing how genes that impact facial shape in humans and mice are providing clues about the genetic basis of orofacial clefting. In this review, I discuss the origins of the FSH, provide an overview of the supporting evidence, and discuss ways in which the FSH can inform our understanding of orofacial clefting.
HDAC Inhibition as Potential Therapeutic Strategy to Restore the Deregulated Immune Response in Severe COVID-19
Authors: Ripamonti Chiara , Spadotto Valeria , Pozzi Pietro , Stevenazzi Andrea , Vergani Barbara , Marchini Mattia , Sandrone Giovanni , Bonetti Emanuele , Mazzarella Luca , Minucci Saverio , Steinkühler Christian , Fossati Gianluca
Published: May 2022

The COVID-19 pandemic has had a devastating impact worldwide and has been a great challenge for the scientific community. Vaccines against SARS-CoV-2 are now efficiently lessening COVID-19 mortality, although finding a cure for this infection is still a priority. An unbalanced immune response and the uncontrolled release of proinflammatory cytokines are features of COVID-19 pathophysiology and contribute to disease progression and worsening. Histone deacetylases (HDACs) have gained interest in immunology, as they regulate the innate and adaptative immune response at different levels. Inhibitors of these enzymes have already proven therapeutic potential in cancer and are currently being investigated for the treatment of autoimmune diseases. We thus tested the effects of different HDAC inhibitors, with a focus on a selective HDAC6 inhibitor, on immune and epithelial cells in in vitro models that mimic cells activation after viral infection. Our data indicate that HDAC inhibitors reduce cytokines release by airway epithelial cells, monocytes and macrophages. This anti-inflammatory effect occurs together with the reduction of monocytes activation and T cell exhaustion and with an increase of T cell differentiation towards a T central memory phenotype. Moreover, HDAC inhibitors hinder IFN-I expression and downstream effects in both airway epithelial cells and immune cells, thus potentially counteracting the negative effects promoted in critical COVID-19 patients by the late or persistent IFN-I pathway activation. All these data suggest that an epigenetic therapeutic approach based on HDAC inhibitors represents a promising pharmacological treatment for severe COVID-19 patients.
Insights Gained Into the Treatment of COVID19 by Pulmonary Surfactant and Its Components
Authors: Li Dan , Wang Xianzheng , Liao Yingzhao , Wang Shouchuan , Shan Jinjun , Ji Jianjian
Published: May 2022

Pulmonary surfactant constitutes an important barrier that pathogens must cross to gain access to the rest of the organism via the respiratory surface. The presence of pulmonary surfactant prevents the dissemination of pathogens, modulates immune responses, and optimizes lung biophysical activity. Thus, the application of pulmonary surfactant for the treatment of respiratory diseases provides an effective strategy. Currently, several clinical trials are investigating the use of surfactant preparations to treat patients with coronavirus disease 2019 (COVID-19). Some factors have been considered in the application of pulmonary surfactant for the treatment COVID-19, such as mechanical ventilation strategy, timing of treatment, dose delivered, method of delivery, and preparation utilized. This review supplements this list with two additional factors: accurate measurement of surfactants in patients and proper selection of pulmonary surfactant components. This review provides a reference for ongoing exogenous surfactant trials involving patients with COVID-19 and provides insight for the development of surfactant preparations for the treatment of viral respiratory infections.
Time-Course of the Innate Immune Response of the Terrestrial Crustacean Porcellio scaber After Injection of a Single Dose of Lipopolysaccharide
Authors: Dolar Andraž , Jemec Kokalj Anita , Drobne Damjana
Published: May 2022

Invertebrates, including crustaceans, rely on cellular and humoral immune responses to protect against extrinsic and intrinsic factors that threaten their integrity. Recently, different immune parameters have been increasingly used as biomarkers of effects of pollutants and environmental change. Here, we describe the dynamics of the innate immune response of the terrestrial crustacean Porcellio scaber to injection of a single dose of lipopolysaccharide (LPS), an important molecular surface component of the outer membrane of Gram-negative bacteria. The aim was to provide a basis for interpretation of change in immune parameters as a result of different challenges, including microplastics and nanoplastics exposure. Changes in total and differential numbers of hemocytes, hemocyte viability, and humoral immune parameters (i.e., phenoloxidase-like activity, nitric oxide levels) were assessed at different times (3, 6, 12, 24, 48 h). An injection of 0.5 μg/μL LPS into the body of P. scaber resulted in a rapid decrease (3 h after LPS injection) in the total number of hemocytes and reduced viability of the hemocytes. This was accompanied by changed proportions of the different hemocyte types, as a decrease in the numbers of semigranulocytes and granulocytes, and a marked increase in the numbers of hyalinocytes. In addition, phenoloxidase-like activity and nitric oxide levels in the hemolymph were increased at 3 h and 6 h, respectively, after the LPS challenge. Forty-eight hours after LPS injection, the immune parameters in the hemolymph of P. scaber had returned to those before the LPS challenge. This suggests that the innate immune system successfully protected P. scaber from the deleterious effects of the LPS challenge. These data indicate the need to consider the dynamics of innate immune responses of P. scaber when effects of infections, pollutants, or environmental changes are studied. We also propose an approach to test the immunocompetence of organisms after different challenges in ecotoxicity studies, based on the dynamics of their immune responses.
Deficiency of Human Adenosine Deaminase Type 2 – A Diagnostic Conundrum for the Hematologist
Authors: Pilania Rakesh Kumar , Banday Aaqib Zaffar , Sharma Saniya , Kumrah Rajni , Joshi Vibhu , Loganathan Sathish , Dhaliwal Manpreet , Jindal Ankur Kumar , Vignesh Pandiarajan , Suri Deepti , Rawat Amit , Singh Surjit
Published: May 2022

Deficiency of adenosine deaminase type 2 (DADA2) was first described in 2014 as a monogenic cause of polyartertitis nodosa (PAN), early onset lacunar stroke and livedo reticularis. The clinical phenotype of DADA2 is, however, very broad and may involve several organ systems. Apart from vasculitis, children may present with i) Hematological manifestations (ii) Lymphoproliferation and iii) Immunodeficiencies. Patients with DADA2 can have variable patterns of cytopenias and bone marrow failure syndromes. Patients with DADA2 who have predominant haematological manifestations are associated with ADA2 gene variants that result in minimal or no residual ADA2 activity. Lymphoproliferation in patients with DADA2 may range from benign lymphoid hyperplasia to lymphoreticular malignancies. Patients may present with generalized lymphadenopathy, splenomegaly, autoimmune lymphoproliferative syndrome (ALPS) like phenotype, Hodgkin lymphoma, T-cell large granular lymphocytic infiltration of bone marrow and multicentric Castleman disease. Immunodeficiencies associated with DADA are usually mild. Affected patients have variable hypogammaglobulinemia, decrease in B cells, low natural killer cells, common variable immunodeficiency and rarely T cell immunodeficiency. To conclude, DADA2 has an extremely variable phenotype and needs to be considered as a differential diagnosis in diverse clinical conditions. In this review, we describe the evolving clinical phenotypes of DADA2 with a special focus on haematological and immunological manifestations.
Identification and Verification of m7G Modification Patterns and Characterization of Tumor Microenvironment Infiltration via Multi-Omics Analysis in Clear Cell Renal Cell Carcinoma
Authors: Dong Kai , Gu Di , Shi Jiazi , Bao Yewei , Fu Zhibin , Fang Yu , Qu Le , Zhu Wentong , Jiang Aimin , Wang Linhui
Published: May 2022

The epigenetic modification of tumorigenesis and progression in neoplasm has been demonstrated in recent studies. Nevertheless, the underlying association of N7-methylguanosine (m7G) regulation with molecular heterogeneity and tumor microenvironment (TME) in clear cell renal cell carcinoma (ccRCC) remains unknown. We explored the expression profiles and genetic variation features of m7G regulators and identified their correlations with patient outcomes in pan-cancer. Three distinct m7G modification patterns, including MGCS1, MGCS2, and MGCS3, were further determined and systematically characterized via multi-omics data in ccRCC. Compared with the other two subtypes, patients in MGCS3 exhibited a lower clinical stage/grade and better prognosis. MGCS1 showed the lowest enrichment of metabolic activities. MGCS2 was characterized by the suppression of immunity. We then established and validated a scoring tool named m7Sig, which could predict the prognosis of ccRCC patients. This study revealed that m7G modification played a vital role in the formation of the tumor microenvironment in ccRCC. Evaluating the m7G modification landscape helps us to raise awareness and strengthen the understanding of ccRCC’s characterization and, furthermore, to guide future clinical decision making.
Clinical, Virological and Immunological Subphenotypes in a Cohort of Early Treated HIV-Infected Children
Authors: Domínguez-Rodríguez Sara , Tagarro Alfredo , Foster Caroline , Palma Paolo , Cotugno Nicola , Zicari Sonia , Ruggiero Alessandra , de Rossi Anita , Dalzini Annalisa , Pahwa Savita , Rinaldi Stefano , Nastouli Eleni , Marcelin Anne-Geneviève , Dorgham Karim , Sauce Delphine , Gartner Kathleen , Rossi Paolo , Giaquinto Carlo , Rojo Pablo
Published: May 2022

Background

Identifying subphenotypes within heterogeneous diseases may have an impact in terms of therapeutic options. In this study, we aim to assess different subphenotypes in children living with human immunodeficiency virus (HIV-1), according to the clinical, virological, and immunological characteristics.

Methods

We collected clinical and sociodemographic data, baseline viral load (VL), CD4 and CD8 count and percentage, age at initiation of ART, HIV DNA reservoir size in peripheral blood mononuclear cells (PBMCs), cell-associated RNA (CA-RNA), ultrasensitive VL, CD4 subsets (T effector CD25+, activated memory cells, Treg cells), humoral-specific HIV response (T-bet B cells), innate response (CD56dim natural killer (NK) cells, NKp46+, perforin), exhaustion markers (PD-1, PD-L1, DNAM), CD8 senescence, and biomarkers for T-lymphocyte thymic output (TREC) and endothelial activation (VCAM). The most informative variables were selected using an unsupervised lasso-type penalty selection for sparse clustering. Hierarchical clustering was performed using Pearson correlation as the distance metric and WARD.D2 as the clustering method. Internal validation was applied to select the best number of clusters. To compare the characteristics among clusters, boxplot and Kruskal Wallis test were assessed.

Results

Three subphenotypes were discovered (cluster1: n=18, 45%; cluster2: n=11, 27.5%; cluster3: n=11, 27.5%). Patients in cluster1 were treated earlier, had higher baseline %CD4, low HIV reservoir size, low western blot score, higher TREC values, and lower VCAM values than the patients in the other clusters. In contrast, cluster3 was the less favorable. Patients were treated later and presented poorer outcomes with lower %CD4, and higher reservoir size, along with a higher percentage of CD8 immunosenescent cells, lower TREC, higher VCAM cytokine, and a higher %CD4 PD-1. Cluster2 was intermediate. Patients were like those of cluster1, but had lower levels of t-bet expression and higher HIV DNA reservoir size.

Conclusions

Three HIV pediatric subphenotypes with different virological and immunological features were identified. The most favorable cluster was characterized by a higher rate of immune reconstitution and a slower disease progression, and the less favorable with more senescence and high reservoir size. In the near future therapeutic interventions for a path of a cure might be guided or supported by the different subphenotypes.
Oral mRNA Vaccines Against Infectious Diseases- A Bacterial Perspective [Invited]
Authors: Jawalagatti Vijayakumar , Kirthika Perumalraja , Lee John Hwa
Published: May 2022

The mRNA vaccines from Pfizer/BioNTech and Moderna were granted emergency approval in record time in the history of vaccinology and played an instrumental role in limiting the pandemic caused by SARS-CoV-2. The success of these vaccines resulted from over 3 decades of research from many scientists. However, the development of orally administrable mRNA vaccine development is surprisingly underexplored. Our group specializing in Salmonella-based vaccines explored the possibility of oral mRNA vaccine development. Oral delivery was made possible by the exploitation of the Semliki Forest viral replicon and Salmonella vehicle for transgene amplification and gene delivery, respectively. Herein we highlight the prospect of developing oral replicon-based mRNA vaccines against infectious diseases based on our recent primary studies on SARS-CoV-2. Further, we discuss the potential advantages and limitations of bacterial gene delivery.
Selective Targeting of IL-15Rα Is Sufficient to Reduce Inflammation
Authors: Meghnem Dihia , Maillasson Mike , Barbieux Isabelle , Morisseau Sébastien , Keita Dalloba , Jacques Yannick , Quéméner Agnès , Mortier Erwan
Published: May 2022

Cytokines are crucial molecules for maintaining the proper functioning of the immune system. Nevertheless, a dysregulation of cytokine expression could be involved in the pathogenesis of autoimmune diseases. Interleukin (IL)-15 is a key factor for natural killer cells (NK) and CD8 T cells homeostasis, necessary to fight cancer and infections but could also be considered as a pro-inflammatory cytokine involved in autoimmune inflammatory disease, including rheumatoid arthritis, psoriasis, along with tumor necrosis factor alpha (TNF-α), IL-6, and IL-1β. The molecular mechanisms by which IL-15 exerts its inflammatory function in these diseases are still unclear. In this study, we generated an IL-15-derived molecule called NANTIL-15 (New ANTagonist of IL-15), designed to selectively inhibit the action of IL-15 through the high-affinity trimeric IL-15Rα/IL-2Rβ/γc receptor while leaving IL-15 signaling through the dimeric IL-2Rβ/γc receptor unaffected. Administrating of NANTIL-15 in healthy mice did not affect the IL-15-dependent cell populations such as NK and CD8 T cells. In contrast, we found that NANTIL-15 efficiently reduced signs of inflammation in a collagen-induced arthritis model. These observations demonstrate that the inflammatory properties of IL-15 are linked to its action through the trimeric IL-15Rα/IL-2Rβ/γc receptor, highlighting the interest of selectively targeting this receptor.
Greek Fire, Poison Arrows, and Scorpion Bombs: How Tumor Cells Defend Against the Siege Weapons of Cytotoxic T Lymphocytes
Authors: McKenzie Brienne , Khazen Roxana , Valitutti Salvatore
Published: May 2022

CD8+cytotoxic T lymphocytes (CTLs) are the main cellular effectors of the adaptive immune response against cancer cells, which in turn have evolved sophisticated cellular defense mechanisms to withstand CTL attack. Herein we provide a critical review of the pertinent literature on early and late attack/defense events taking place at the CTL/target cell lytic synapse. We examine the earliest steps of CTL-mediated cytotoxicity (“the poison arrows”) elicited within seconds of CTL/target cell encounter, which face commensurately rapid synaptic repair mechanisms on the tumor cell side, providing the first formidable barrier to CTL attack. We examine how breach of this first defensive barrier unleashes the inextinguishable “Greek fire” in the form of granzymes whose broad cytotoxic potential is linked to activation of cell death executioners, injury of vital organelles, and destruction of intracellular homeostasis. Herein tumor cells deploy slower but no less sophisticated defensive mechanisms in the form of enhanced autophagy, increased reparative capacity, and dysregulation of cell death pathways. We discuss how the newly discovered supra-molecular attack particles (SMAPs, the “scorpion bombs”), seek to overcome the robust defensive mechanisms that confer tumor cell resistance. Finally, we discuss the implications of the aforementioned attack/defense mechanisms on the induction of regulated cell death (RCD), and how different contemporary RCD modalities (including apoptosis, pyroptosis, and ferroptosis) may have profound implications for immunotherapy. Thus, we propose that understanding and targeting multiple steps of the attack/defense process will be instrumental to enhance the efficacy of CTL anti-tumor activity and meet the outstanding challenges in clinical immunotherapy.
Integration of Tumor Microenvironment in Patient-Derived Organoid Models Help Define Precision Medicine of Renal Cell Carcinoma
Authors: Wang Bingran , Xue Yizheng , Zhai Wei
Published: May 2022

Renal cell carcinoma (RCC) is a common urological tumor, with a poor prognosis, as the result of insensitivity to chemotherapy and radiotherapy. About 20%–30% of patients with RCC have metastasis at the first diagnosis, so only systemic treatment is possible. Due to the heterogeneity of renal tumors, responses to drugs differ from person to person. Consequently, patient-derived organoid, highly recapitulating tumor heterogeneity, becomes a promising model for high-throughput ex vivo drug screening and thus guides the drug choice of patients with RCC. Systemic treatment of RCC mainly targets the tumor microenvironment, including neovasculature and immune cells. We reviewed several methods with which patient-derived organoid models mimic the heterogeneity of not only tumor epithelium but also the tumor microenvironment. We further discuss some new aspects of the development of patient-derived organoids, preserving in vivo conditions in patients with RCC.
CMOS-MEMS Oscillator Architecture and Phase Noise: A Mini-Review
Authors: Li Ming-Huang
Published: May 2022

Over the past two decades, the advancement in microelectromechanical systems (MEMS) has been making headway in the development of miniaturized mechanical structures with integrated electronics. By adopting the existing layer in the complementary metal–oxide–semiconductor (CMOS) fabrication platform, the so-called “CMOS-MEMS” technology offers an intrinsic circuit-MEMS integration scheme, paving the way to realize monolithic micromechanical oscillators for frequency control and sensing applications. To enhance the functionality of the oscillator, it is cardinal to understand the secrets behind the resonator and circuit design techniques to generate high spectral purity signals. As the oscillator characteristics heavily depend on the resonator’s motional parameters, the circuit configuration is determined in accordance with the post-CMOS processing technology and the mode shape of the resonator. In this mini-review, we attempt to summarize and appraise studies related to the design and optimization of CMOS-MEMS oscillators and to give directions for future researchers in terms of phase noise.
A Somatic Mutation Signature Predicts the Best Overall Response to Anti-programmed Cell Death Protein-1 Treatment in Epidermal Growth Factor Receptor/Anaplastic Lymphoma Kinase-Negative Non-squamous Non-small Cell Lung Cancer
Authors: Peng Jie , Xiao Lushan , Zou Dan , Han Lijie
Published: May 2022

Background

We aimed to exploit a somatic mutation signature (SMS) to predict the best overall response to anti-programmed cell death protein-1 (PD-1) therapy in non-small cell lung cancer (NSCLC).

Methods

Tumor samples of 248 patients with epidermal growth factor receptor (EGFR)/anaplastic lymphoma kinase (ALK)-negative non-squamous NSCLC treated with anti-PD-1 were molecularly tested by targeted next-generation sequencing or whole exome sequencing. On the basis of machine learning, we developed and validated a predictive model named SMS using the training (n = 83) and validation (n = 165) cohorts.

Results

The SMS model comprising a panel of 15 genes (TP53, PTPRD, SMARCA4, FAT1, MGA, NOTCH1, NTRK3, INPP4B, KMT2A, PAK1, ATRX, BCOR, KDM5C, DDR2, and ARID1B) was built to predict best overall response in the training cohort. The areas under the curves of the training and validation cohorts were higher than those of tumor mutational burden and PD-L1 expression. Patients with SMS-high in the training and validation cohorts had poorer progression-free survival [hazard ratio (HR) = 6.01, P < 0.001; HR = 3.89, P < 0.001] and overall survival (HR = 7.60, P < 0.001; HR = 2.82, P < 0.001) than patients with SMS-low. SMS was an independent factor in multivariate analyses of progression-free survival and overall survival (HR = 4.32, P < 0.001; HR = 3.07, P < 0.001, respectively).

Conclusion

This study revealed the predictive value of SMS for immunotherapy best overall response and prognosis in EGFR/ALK-negative non-squamous NSCLC as a potential biomarker in anti-PD-1 therapy.
Exosome Mediated Cytosolic Cisplatin Delivery Through Clathrin-Independent Endocytosis and Enhanced Anti-cancer Effect via Avoiding Endosome Trapping in Cisplatin-Resistant Ovarian Cancer
Authors: Zhou Guannan , Gu Yuanyuan , Zhu Zhongyi , Zhang Hongdao , Liu Wei , Xu Beiying , Zhou Fangyue , Zhang Menglei , Hua Keqin , Wu Ligang , Ding Jingxin
Published: May 2022

Background

Ovarian carcinoma is one of the most common gynecologic malignancies, cisplatin resistance has become a key obstacle to the successful treatment of ovarian cancer because ovarian carcinomas are liable to drug resistance. To find an effective drug carrier is an urgent need.

Methods

Exosomes and loading-cisplatin exosomes are isolated using differential centrifugation and characterized by transmission, electron, nanoparticle tracking analysis. The anti-cancer effect of cisplatin was detected under the circumstance of delivered by exosomes or without exosomes in vitro and in vivo. Using proteome analysis and bioinformatics analysis, we further discovered the pathways in exosomes delivery process. We employed a con-focal immunofluorescence analysis, to evaluate the effects of milk-exosomes deliver the cisplatin via avoiding endosomal trapping.

Results

Exosomes and exosome-cisplatin were characterized including size, typical markers including CD63, Alix and Tsg101. The anti-cancer effect of cisplatin was enhanced when delivered by exosome in vitro and in vivo. Mechanistic studies shown that exosomes deliver cisplatin mostly via clathrin-independent endocytosis pathway. Exosomes deliver cisplatin into cisplatin-resistant cancer cells clathrin-independent endocytosis and enhance the anti-cancer effect through avoiding endosome trapping.

Conclusion

Cisplatin could be delivered by exosome through clathrin-independent endocytosis, and could evade the endosome trapping, diffused in the cytosol evenly. Our study clarifies the mechanism of exosomes mediated drug delivery against resistant cancer, indicates that exosomes can be a potential nano-carrier for cisplatin against cisplatin resistant ovarian cancer, which validates and enriches the theory of intracellular exosome trafficking.
Utility of Baseline Transcriptomic Analysis of Rheumatoid Arthritis Synovium as an Indicator for Long-Term Clinical Outcomes
Authors: Anaparti Vidyanand , Wiens Dana , O'Neil Liam J. , Hubbard Erika , Robl Robert , Smolik Irene , Hitchon Carol , Lipsky Peter E. , El-Gabalawy Hani
Published: May 2022

Objective:

Rheumatoid arthritis is a chronic inflammatory autoimmune disease that can lead to synovial damage, persistent joint pain, and functional disability. Our objective was to evaluate baseline synovial transcriptome from early inflammatory arthritis patients (EIA) and identify pretreatment biomarkers that could potentially provide insights into long-term functional outcomes of rheumatoid arthritis (RA).

Methods

Synovial biopsies from clinically inflamed knee joints were procured from either 17 EIA patients before initiation of disease modifying anti-rheumatic drug (DMARD) therapy (DMARD-naïve EIA) using the minimally invasive closed needle biopsy technique or advanced RA patients undergoing arthroplasty. Affymetrix Human Genome U133 Plus 2 microarray platform was used to profile the synovial transcriptome. The cohort was followed clinically for a median of 12.3 years, and patient data was collected at each visit. Short-term and long-term clinical outcomes were determined by assessing RA-associated clinical parameters Statistical adjustments were made to account for asynchronous clinical visits and duration of follow up.

Results

Based on the transcriptomic analysis, we identified 5 differentially expressed genes (DEGs), including matrix metalloproteinase (MMP)-1 (fibroblast collagenase) and MMP-3 (stromelysin-1) in DMARD-naïve EIA patients, relative to advanced RA patients (q < 0.05). Dichotomous expression of MMP-1 and MMP-3 mRNA and protein was confirmed by qPCR and immunohistochemistry respectively, based on which DMARD-naïve EIA subjects were classified as MMP-high or MMP-low. Hierarchical clustering of transcriptomic data identified 947 DEGs between MMP-high and MMP-low cohorts. Co-expression and IPA analysis of DEGs in the MMP-high cohort showed an enrichment of genes that participated in metabolic or biochemical functions and intracellular immune signaling were regulated through NF-κB and β-catenin complexes and correlated with markers of systemic inflammation. Analysis of short-term clinical outcomes in MMP-high cohort showed a significant reduction in the DAS-CRP scores relative to baseline (P <0.001), whereas area under the curve analyses of modified HAQ (mHAQ) scores correlated negatively with baseline MMP-1 (R = −0.59, P = 0.03). Further, longitudinal mHAQ scores, number of swollen joints, number of DMARDs and median follow-up duration appeared to be higher in MMP-low cohort.

Conclusion

Overall, our results indicate that the gene expression profiling of synovial biopsies obtained at the DMARD-naive stage in patients with EIA categorizes them into subsets with varying degrees of inflammation and can predict the future of long-term clinical outcome.
Applying Information Gain to Explore Factors Affecting Small-Incision Lenticule Extraction: A Multicenter Retrospective Study
Authors: Liang Shuang , Ji Shufan , Liu Xiao , Chen Min , Lei Yulin , Hou Jie , Li Mengdi , Zou Haohan , Peng Yusu , Ma Zhixing , Liu Yuanyuan , Jhanji Vishal , Wang Yan
Published: May 2022

Purpose

This retrospective study aimed to identify the key factors influencing postoperative refraction after small-incision lenticule extraction (SMILE) using information gain.

Methods

This study comprised 2,350 eyes of 1,200 patients who underwent SMILE using a Visumax 500-kHz femtosecond laser (Carl Zeiss Meditec AG) in three ophthalmic centers: Tianjin Eye Hospital (center A), Jinan Mingshui Eye Hospital (center B), and Qingdao Eye Hospital (center C). Anterior segment features, including corneal curvature and central corneal thickness (CCT), were obtained from Pentacam HR (Oculus, Wetzlar, Germany). Information gain was calculated to analyze the importance of features affecting postoperative refraction.

Results

Preoperative and postoperative mean spherical equivalent (SE) refraction were −5.00 (−6.13, −3.88) D and 0.00 (−0.25, 0.13) D, respectively. None of the patients lost more than two lines of corrected distance visual acuity. The safety index was 1.32 ± 0.24, 1.03 ± 0.08, and 1.13 ± 0.16 in centers A, B, and C, respectively. The efficacy index was 1.31 ± 0.25, 1.02 ± 0.08, and 1.13 ± 0.17 in centers A, B, and C, respectively. At least 95% of the eyes were within ±1.00 D of the attempted correction. Postoperative refraction was related to preoperative spherical diopter refraction (r = 0.369, p < 0.001), preoperative SE (r = 0.364, p < 0.001), maximum lenticule thickness (r = −0.311, p < 0.001), preoperative uncorrected distance visual acuity (r = 0.164, p < 0.001), residual stromal thickness (r = 0.139, p < 0.001), preoperative mean anterior corneal curvature (r = −0.127, p < 0.001), preoperative flattest anterior corneal curvature (r = −0.122, p < 0.001), nomogram (r = −0.100, p < 0.001) and preoperative CCT (r = −0.058, p = 0.005).

Conclusions

SMILE was considered a safe and effective procedure for correcting myopia. Based on information gain, postoperative refraction was influenced by preoperative mean anterior corneal curvature, CCT, refraction, and residual stromal thickness.
Comparative Genomics of Prunus-Associated Members of the Pseudomonas syringae Species Complex Reveals Traits Supporting Co-evolution and Host Adaptation
Authors: Ruinelli Michela , Blom Jochen , Smits Theo H. M. , Pothier Joël F.
Published: May 2022

Members of the Pseudomonas syringae species complex cause symptoms that are ranging from leaf spots to cankers on a multitude of plant species, including some of the genus Prunus. To date, a total of two species of the P. syringae species complex and six different pathovars have been associated with diseases on Prunus spp., which were shown to belong to different phylogenetic units (phylogroups, PG) based on sequence similarity of housekeeping genes or whole genomes, suggesting that virulence to Prunus spp. may be the result of convergent pathoadaptation. In this study, a comparative genomics approach was used to determine genes significantly associated with strains isolated from Prunus spp. across a phylogeny of 97 strains belonging to the P. syringae species complex. Our study revealed the presence of a set of orthologous proteins which were significantly associated with strains isolated from Prunus spp. than in strains isolated from other hosts or from non-agricultural environments. Among them, the type III effector HopAY predicted to encode for a C58 cysteine protease was found to be highly associated with strains isolated from Prunus spp. and revealed patterns supporting co-evolution and host adaptation.
Comparative Proteomic Analysis of Psychrophilic vs. Mesophilic Bacterial Species Reveals Different Strategies to Achieve Temperature Adaptation
Authors: García-Descalzo Laura , García-López Eva , Cid Cristina
Published: May 2022

The old debate of nature (genes) vs. nurture (environmental variables) is once again topical concerning the effect of climate change on environmental microorganisms. Specifically, the Polar Regions are experiencing a drastic increase in temperature caused by the rise in greenhouse gas emissions. This study, in an attempt to mimic the molecular adaptation of polar microorganisms, combines proteomic approaches with a classical microbiological analysis in three bacterial speciesShewanella oneidensis,Shewanella frigidimarina, andPsychrobacter frigidicola. Both shewanellas are members of the same genus but they live in different environments. On the other hand,Shewanella frigidimarinaandPsychrobacter frigidicolashare the same natural environment but belong to a different genus. The comparison of the strategies employed by each bacterial species estimates the contribution of genome vs. environmental variables in the adaptation to temperature. The results show a greater versatility of acclimatization for the genusShewanellawith respect toPsychrobacter. Besides,S. frigidimarinawas the best-adapted species to thermal variations in the temperature range 4–30°C and displayed several adaptation mechanisms common with the other two species. Regarding the molecular machinery used by these bacteria to face the consequences of temperature changes, chaperones have a pivoting role. They form complexes with other proteins in the response to the environment, establishing cooperation with transmembrane proteins, elongation factors, and proteins for protection against oxidative damage.
Third Generation Genome Sequencing Reveals That Endobacteria in Nematophagous Fungi Esteya vermicola Contain Multiple Genes Encoding for Nematicidal Proteins
Authors: Wang Ruizhen , Dong Leiming , Chen Yuequ , Wang Shuai , Qu Liangjian
Published: May 2022

Esteya vermicola is the first recorded endoparasitic nematophagous fungus with high infectivity capacity, attacking the pinewood nematode Bursaphelenchus xylophilus which causes pine wilt disease. Endosymbionts are found in the cytoplasm of E. vermicola from various geographical areas. We sequenced the genome of endobacteria residing in E. vermicola to discover possible biological functions of these widespread endobacteria. Multilocus phylogenetic analyses showed that the endobacteria form a previously unidentified lineage sister to Phyllobacterium myrsinacearum species. The number of genes in the endobacterium was 4542, with 87.8% of the proteins having a known function. It contained a high proportion of repetitive sequences, as well as more Acyl-CoA synthetase genes and genes encoding the electron transport chain, compared with compared with plant-associated P. zundukense Tri 48 and P. myrsinacearum DSM 5893. Thus, this symbiotic bacterium is likely to be more efficient in regulating gene expression and energy release. Furthermore, the endobacteria in nematophagous fungi Esteya vermicola contained multiple nematicidal subtilase/subtilisin encoding genes, so it is likely that endobacteria cooperate with the host to kill nematodes.