bluuebunny/crossref_metadata_2025 huggingface dataset:
Governance and Quintuple Helix innovation model: Insights from the local government of East Luwu Regency, Indonesia
Authors: Abdillah Abdillah , Widianingsih Ida , Buchari Rd Ahmad , Mustari Nuryanti , Saleh Syafiuddin
Published: December 2022

Climate change issues pose complex social and ecological challenges to rural communities in East Luwu Regency, Indonesia. This can be overcome through a collaborative, sustainable, and distributed innovation process for regional resilience and independence in each innovation sector. This study examines the concept of rural living as an inter-organizational interaction design and the process of developing sustainable rural innovation, where multi-stakeholder interaction forms the Quintuple Helix innovation model through a multidimensional case study design that focuses on the concept of innovation participation, knowledge production, innovation ecosystem as a social subsystem system, and socioecological transition toward developing independent rural areas, sustainability of rural innovation programs, and disaster preparedness in East Luwu Regency. This research method is qualitative-explorative with a case study approach exploring the social and ecological systems of rural communities in East Luwu Regency, Indonesia to provide a deeper understanding of the rural innovation process to address socio-ecological challenges through the importance of government-public-private-university synergy and its context in the Magani and Sorowako Villages, East Luwu Regency. The results of this study indicate that the strength of the innovation driver resulting from the cooperation between the East Luwu Government and PT Vale Tbk is the key to the sustainability of village innovations that encourage village innovation and village community participation in the village innovation process so that it has an impact on village community independence and environmental sustainability in East Luwu Regency. However, village innovation in East Luwu Regency still needs to be improved in terms of communication and coordination between actors and sectors.
Case report: Pacemaker lost capture after acute myocardial infarction in a patient with left circumflex coronary artery occlusion
Authors: Wu Zhihong , Tang Jianjun , Zhu Qingyi , Hu Lin , Liu Zhenjiang , Li Xuping , Liu Qiming , Zhou Shenghua , Chen Mingxian
Published: December 2022

A 71-year-old female with a dual-chamber pacemaker presented to our hospital complaining of repeated chest pain. She was diagnosed with unstable angina. On day 7, the patient suddenly suffered cardiopulmonary arrest due to an inferior ST segment elevation myocardial infarction (STEMI). Pacemaker lost capture was suspected and was later confirmed by a pacemaker check with a high pacing threshold and a low sensing parameter. Emergency coronary angiography revealed that a large filling defect remained due to an extensive thrombus in the proximal left circumflex (LCX) with thrombolysis in myocardial infarction (TIMI) grade 2 flow, and then a repeat thrombus aspiration was performed. After reperfusion, the parameters of the right ventricular lead were gradually returned. We conclude that the loss of the right ventricular lead pacing occurred in this case of acute coronary syndrome (ACS) induced by an LCX thrombus due to an LCX supplying the right ventricular septal.
The effectiveness of a mobile intervention to reduce young adults’ alcohol consumption to not exceed low-risk drinking guidelines
Authors: Schulte Mieke H.J. , Boumparis Nikolaos , Kleiboer Annet , Wind Tim R. , Olff Miranda , Huizink Anja C. , Riper Heleen
Published: December 2022

Background

Young adults’ drinking habits often exceed low-risk drinking guidelines. As young adults show increased access, use, and interest in personalized content related to physical and mental well-being, mobile applications might be a suitable tool to reach this target group. This study investigates the effectiveness of “Boozebuster”, a self-guided mobile application incorporating various therapeutic principles to reduce young adults’ alcohol consumption to not exceeding low-risk drinking guideline levels, compared to an educational website condition.

Method

Young adults aged 18–30 wanting to reduce their alcohol consumption entered a two-arm, parallel-group RCT. There were no minimum drinking severity inclusion criteria. Primary outcomes included alcohol consumption quantity and frequency. Secondary outcomes included binge drinking frequency and alcohol-related problem severity. Baseline, 6-week postbaseline, and 3-month post-baseline assessments were analyzed using linear mixed model analyses. Sex, treatment adherence, experienced engagement and motivation to change alcohol use behavior were investigated as moderators. Sub-group analyses contained problem drinkers and binge drinkers.

Results

503 participants were randomized to the intervention or control condition. Results showed no intervention effects on primary or secondary outcomes compared to the control group. Both groups showed within-group reductions on all outcomes. Sub-group analyses in problem drinkers or binge drinkers showed similar results. Motivation to change drinking behavior and experienced engagement with the application significantly moderated the intervention effect regarding the quantity or frequency of alcohol consumption, respectively. Exploratory analyses showed that participants who indicated they wanted to change their drinking patterns during the initial PNF/MI module showed a significantly greater reduction in drinking quantity compared to those who indicated not wanting to change their drinking patterns.

Conclusion

The intervention group did not show a greater reduction in alcohol-related outcomes compared to the control group, but both groups showed a similar decrease. Potential explanations include similar effectiveness of both condition due to using a minimal active control in participants predominantly in the action stage of motivation to change. Future research should further explore the effectiveness of using mobile application to reduce young adults’ drinking behavior to not exceed low-risk drinking guideline levels and identify factors that motivate participants to engage with such an intervention.
Rethinking conceptions of body image in group fitness education, culture, and contexts: Recommendations for perspective transformation and innovations in instructional methods
Authors: Dobrich Emily O. R.
Published: December 2022

This article examines the situation of group fitness instructors with particular attention to the implications of the influence of fitness culture on body-related norms which shape instructors’ self-perceived conceptions of body image. Of particular interest is the consideration of how self-perception influences an instructor’s performance, and their ability to educate and motivate their class participants. Evidence will show that the most popular ways that body image is incorporated into and represented within the group fitness setting are limiting and misguided, and there are better methods for instruction that fitness professionals and the industry can follow. Recommendations for practice and suggestions for interventions to encourage adequate body satisfaction in the group fitness instructor’s context will be provided for both individual and collective levels of action. This will include what instructors can do at an individual level to improve their self-perceptions and professional practice and support themselves and their peers; what can be done in gyms and fitness facilities to improve community support for instructors; and what can be done at the fitness industry level to encourage a cultural shift in body-related norms and expectations.
Like our foremothers survived: Self-education, direct confrontation, and humor as resistance coping in Black womxn and femme college student being
Authors: Luney LeAnna T.
Published: December 2022

In our continued study of Blackness and being, we must emphasize the quotidian—or everyday—strategies that young Black womxn and femmes employ to cope with anti-Black gendered racism and its psychological impact at historically and predominantly white institutions. As such, the purpose of this article is to give prominence to the resistance types of coping strategies that Black womxn and femme college students used to maintain their dignity at a predominantly white university of the American West, where the psychological aftermath of anti-Black gendered racism remains hidden under dense layers of neoliberalism, affluence, faux progressivism, and whiteness. I approach this topic from the conceptual perspective of Blackness and being at the nexus of gender by combining discourses on the ontologies of Blackness, and Black feminist thought and epistemology. In the study that informs this article, I utilized qualitative mixed methods—one-on-one interviews, focus group interviews, and participant observation. Like our foremothers whose survival was predicated on the subtle and purposeful coping strategies they engaged, Black womxn and femme college students’ resistance coping styles were demonstrated in the everyday presence of anti-Black gendered racism. Findings reveal that Black womxn and femme undergraduate students demonstrated three main types of resistance coping when experiencing anti-Black gendered racism: (1) self-education; (2) direct confrontation with aggressors (e.g., racists, sexists, homophobes, elitists); and (3) humor. I conclude with recommendations on transformative justice, monetary trusts, longitudinal data collection, and critical curriculum at historically and predominantly white educational institutions.
Overexpression of growth hormone improved hepatic glucose catabolism and relieved liver lipid deposition in common carp (Cyprinus carpio L.) fed a high-starch diet
Authors: Wu Yunya , Li Rui , Wu Xingxing , Guo Wei , Zhong Wenrong , Li Yongming , Song Yanlong , Tao Binbin , Chen Ji , Han Dong , Xie Shouqi , Wang Yaping , Zhu Zuoyan , Hu Wei
Published: December 2022

Growth hormone (GH) is important for regulating insulin secretion and carbohydrate metabolism, and its role in mammalian models of diabetes is relatively worked out. Although some fish species were used as models for diabetes research, the effects of GH on insulin and glucose catabolism and anabolism in these models remain to be clarified. In this study, we investigated the effect of GH on insulin and glucose catabolism and anabolism in an omnivorous fish using GH transgenic (T) common carp that consistently overexpressed GH and wild-type (WT) common carp. We compared the intestinal morphology, and digestive and absorptive capacity of fish fed commercial feed. We also analyzed the growth performance, insulin level, glucose catabolism and anabolism, lipid deposition, and lipid catabolism and anabolism in T carp and WT carp fed diets containing either 30% or 40% starch. In the intestine of T carp, α-amylase activity was enhanced, the number of goblet cells and intestinal villi surface area was increased, and the expression level of glucose transport protein-related genes (glut2 and sglt1) was upregulated when compared to these indicators in WT carp. When fed either a normal or high-starch diet, the growth performance of T carp was better than that of WT carp. Compared with WT carp, serum insulin was increased and glucose was decreased, hepatic expression level of igf-1 and glycolysis-related genes was increased, and the activity level of a hepatic enzyme related to glycolysis was enhanced in T carp. When fed with a high-starch diet, the serum alanine aminotransferase activity, hepatic lipid content, and malondialdehyde content were significantly lower in T carp than in WT carp. These results indicated that overexpression of GH (1) enhanced carbohydrate digestion and absorption in the carp intestine, (2) did not induce insulin resistance and improved glucose catabolism and utilization in carp, and (3) relieved liver lipid deposition. Our data might provide new insights into potential ways to improve glucose utilization in fish and diabetes treatments.
Advances in the treatment of secondary and tertiary hyperparathyroidism
Authors: Zhang Li-Xi , Zhang Ben , Liu Xu-Yao , Wang Zi-Ming , Qi Peng , Zhang Tong-Yue , Zhang Qiang
Published: December 2022

Secondary hyperparathyroidism (SHPT) and tertiary hyperparathyroidism (THPT) are common and complicated clinical endocrine diseases. The parathyroid glands maintain endocrine homeostasis by secreting parathyroid hormone to regulate blood calcium levels. However, structural alterations to multiple organs and systems occur throughout the body due to hyperactivity disorder in SHPT and THPT. This not only decreases the patients’ quality of life, but also affects mortality. Since current treatments for these diseases remains unclear, we aimed to develop a comprehensive review of advances in the treatment of SHPT and THPT according to the latest relevant researches.
Zebrafish endochondral growth zones as they relate to human bone size, shape and disease
Authors: Le Pabic Pierre , Dranow Daniel B. , Hoyle Diego J. , Schilling Thomas F.
Published: December 2022

Research on the genetic mechanisms underlying human skeletal development and disease have largely relied on studies in mice. However, recently the zebrafish has emerged as a popular model for skeletal research. Despite anatomical differences such as a lack of long bones in their limbs and no hematopoietic bone marrow, both the cell types in cartilage and bone as well as the genetic pathways that regulate their development are remarkably conserved between teleost fish and humans. Here we review recent studies that highlight this conservation, focusing specifically on the cartilaginous growth zones (GZs) of endochondral bones. GZs can be unidirectional such as the growth plates (GPs) of long bones in tetrapod limbs or bidirectional, such as in the synchondroses of the mammalian skull base. In addition to endochondral growth, GZs play key roles in cartilage maturation and replacement by bone. Recent studies in zebrafish suggest key roles for cartilage polarity in GZ function, surprisingly early establishment of signaling systems that regulate cartilage during embryonic development, and important roles for cartilage proliferation rather than hypertrophy in bone size. Despite anatomical differences, there are now many zebrafish models for human skeletal disorders including mutations in genes that cause defects in cartilage associated with endochondral GZs. These point to conserved developmental mechanisms, some of which operate both in cranial GZs and limb GPs, as well as others that act earlier or in parallel to known GP regulators. Experimental advantages of zebrafish for genetic screens, high resolution live imaging and drug screens, set the stage for many novel insights into causes and potential therapies for human endochondral bone diseases.
On the optimal cathode catalyst layer for polymer electrolyte fuel cells: Bimodal pore size distributions with functionalized microstructures
Authors: García-Salaberri Pablo A. , Sánchez-Ramos Arturo , Das Prodip K.
Published: December 2022

A high advancement has been achieved in the design of proton exchange membrane fuel cells (PEMFCs) since the development of thin-film catalyst layers (CLs). However, the progress has slowed down in the last decade due to the difficulty in reducing Pt loading, especially at the cathode side, while preserving high stack performance. This situation poses a barrier to the widespread commercialization of fuel cell vehicles, where high performance and durability are needed at a reduced cost. Exploring the technology limits is necessary to adopt successful strategies that can allow the development of improved PEMFCs for the automotive industry. In this work, a numerical model of an optimized cathode CL is presented, which combines a multiscale formulation of mass and charge transport at the nanoscale(∼10nm)and at the layer scale(∼1μm). The effect of exterior oxygen and ohmic transport resistances are incorporated through mixed boundary conditions. The optimized CL features a vertically aligned geometry of equally spaced ionomer pillars, which are covered by a thin nanoporous electron-conductive shell. The interior surface of cylindrical nanopores is catalyzed with a Pt skin (atomic thickness), so that triple phase points are provided by liquid water. The results show the need to develop thin CLs with bimodal pore size distributions and functionalized microstructures to maximize the utilization of water-filled nanopores in which oxygen transport is facilitated compared with ionomer thin films. Proton transport across the CL must be assisted by low-tortuosity ionomer regions, which provide highways for proton transport. Large secondary pores are beneficial to facilitate oxygen distribution and water removal. Ultimate targets set by the U.S. Department of Energy and other governments can be achieved by an optimization of the CL microstructure with a high electrochemical surface area, a reduction of the oxygen transport resistance from the channel to the CL, and an increase of the catalyst activity (or maintaining a similar activity with Pt alloys). Carbon-free supports (e.g., polymer or metal) are preferred to avoid corrosion and enlarge durability.
A novel necroptosis-related lncRNA based signature predicts prognosis and response to treatment in cervical cancer
Authors: Du Xinyi , Pu Xiaowen , Wang Xintao , Zhang Yuchen , Jiang Ting , Ge Yanjun , Zhu Haiyan
Published: December 2022

Background: Necroptosis has been demonstrated to play a crucial role in the prognosis prediction and assessment of treatment outcome in cancers, including cervical cancer. The purpose of this study was to explore the potential prognostic value of necroptosis-related lncRNAs and their relationship with immune microenvironment and response to treatment in cervical cancer.

Methods: Data from The Cancer Genome Atlas (TCGA) were collected to obtain synthetic data matrices. Necroptosis-related lncRNAs were identified by Pearson Correlation analysis. Univariate Cox and multivariate Cox regression analysis and Lasso regression were used to construct a necroptosis-related LncRNAs signature. Kaplan-Meier analysis, univariate and multivariate Cox regression analyses, receiver operating characteristic (ROC) curve, nomogram, and calibration curves analysis were performed to validate this signature. Gene set enrichment analyses (GSEA), immunoassays, and the half-maximal inhibitory concentration (IC50) were also analyzed.

Results: Initially, 119 necroptosis-related lncRNAs were identified based on necroptosis-related genes and differentially expressed lncRNAs between normal and cervical cancer samples. Then, a prognostic risk signature consisting of five necroptosis-related lncRNAs (DDN-AS1, DLEU1, RGS5, RUSC1-AS1, TMPO-AS1) was established by Cox regression analysis, and LASSO regression techniques. Based on this signature, patients with cervical cancer were classified into a low- or high-risk group. Cox regression confirmed this signature as an independent prognostic predictor with an AUC value of 0.789 for predicting 1-year OS. A nomogram including signature, age, and TNM stage grade was then established, and showed an AUC of 0.82 for predicting 1-year OS. Moreover, GSEA analysis showed that immune-related pathways were enriched in the low-risk group; immunoassays showed that most immune cells, ESTIMAT scores and immune scores were negatively correlated with risk score and that the expression of immune checkpoint-proteins (CD27, CD48, CD200, and TNFRSF14) were higher in the low-risk group. In addition, patients in the low-risk group were more sensitive to Rucaparib, Navitoclax and Crizotinib than those in the high-risk group.

Conclusion: We established a novel necroptosis-related lncRNA based signature to predict prognosis, tumor microenvironment and response to treatment in cervical cancer. Our study provides clues to tailor prognosis prediction and individualized immunization/targeted therapy strategies.
Graphene quantum dots induce cascadic apoptosis via interaction with proteins associated with anti-oxidation after endocytosis by Trypanosoma brucei
Authors: Xie Yiwei , Liang Hongrui , Jiang Ning , Liu Dingyuan , Zhang Naiwen , Li Qilong , Zhang Kai , Sang Xiaoyu , Feng Ying , Chen Ran , Zhang Yiwei , Chen Qijun
Published: December 2022

Trypanosoma brucei, the pathogen causing African sleeping sickness (trypanosomiasis) in humans, causes debilitating diseases in many regions of the world, but mainly in African countries with tropical and subtropical climates. Enormous efforts have been devoted to controlling trypanosomiasis, including expanding vector control programs, searching for novel anti-trypanosomial agents, and developing vaccines, but with limited success. In this study, we systematically investigated the effect of graphene quantum dots (GQDs) on trypanosomal parasites and their underlying mechanisms. Ultrasmall-sized GQDs can be efficiently endocytosed by T. brucei and with no toxicity to mammalian-derived cells, triggering a cascade of apoptotic reactions, including mitochondrial disorder, intracellular reactive oxygen species (ROS) elevation, Ca2+ accumulation, DNA fragmentation, adenosine triphosphate (ATP) synthesis impairment, and cell cycle arrest. All of these were caused by the direct interaction between GQDs and the proteins associated with cell apoptosis and anti-oxidation responses, such as trypanothione reductase (TryR), a key protein in anti-oxidation. GQDs specifically inhibited the enzymatic activity of TryR, leading to a reduction in the antioxidant capacity and, ultimately, parasite apoptotic death. These data, for the first time, provide a basis for the exploration of GQDs in the development of anti-trypanosomials.
A therapeutic vaccine strategy to prevent Pneumocystis pneumonia in an immunocompromised host in a non-human primate model of HIV and Pneumocystis co-infection
Authors: Rabacal Whitney , Schweitzer Finja , Kling Heather M. , Buzzelli Lizabeth , Rayens Emily , Norris Karen A.
Published: December 2022

Introduction

Pneumocystis is a ubiquitous fungal pathogen that causes pneumonia (PCP) and pulmonary sequelae in HIV-infected individuals and other immunocompromised populations. With the success of anti-retroviral therapy for HIV-infected individuals the frequency of PCP in that population has decreased, however, PCP remains a significant cause of morbidity and mortality in individuals with hematologic and solid malignancies, and in individuals treated with immunosuppressive therapies for autoimmune diseases, and following bone marrow and solid organ transplantation. Despite the clinical need, there is no approved vaccine to prevent PCP in vulnerable populations. The ultimate goal of the field is to develop an effective vaccine that can overcome immune deficits in at risk populations and induce long-lasting protective immunity to Pneumocystis. Toward this goal, our laboratory has established a model of PCP co-infection in simian immunodeficiency virus (SIV)-infected non-human primates (NHP) and identified a recombinant protein sub-unit vaccine, KEX1, that induces robust anti-Pneumocystis immunity in immune-competent macaques that is durable and prevents PCP following simian immunodeficiency virus (SIV)-induced immunosuppression. Type I, or invariant natural killer T (iNKT) cells have the potential to provide B cell help under conditions of reduced CD4+ T cell help.

Methods

In the present study, we used the SIV model of HIV infection to address whether therapeutic vaccination with the iNKT cell-activating adjuvant α-galactosylceramide (α-GC) and KEX1 (α-GC+KEX1) can effectively boost anti-Pneumocystis humoral immunity following virus-induced immunosuppression.

Results

Immunization of antigen-experienced NHPs with α-GC+KEX1 during the early chronic phase of SIV-infection significantly boosted anti-Pneumocystis humoral immunity by increasing memory B cells and antibody titers, and enhanced titer durability during SIV-induced immunosuppression. This therapeutic vaccination strategy boosted anti-Pneumocystis immune responses during SIV-infection and contributed to protection against Pneumocystis co-infection in KEX1-vaccinated macaques.

Conclusion

These studies present a novel strategy for stimulating durable anti-Pneumocystis humoral immunity in the context of complex, chronic SIV-induced immunosuppression and may be further applied to immunization of other immunosuppressed populations, and toward other common recall antigens.
Hematologic dysfunction in cancer: Mechanisms, effects on antitumor immunity, and roles in disease progression
Authors: Plackoska Viktoria , Shaban Dania , Nijnik Anastasia
Published: December 2022

With the major advances in cancer immunology and immunotherapy, it is critical to consider that most immune cells are short-lived and need to be continuously replenished from hematopoietic stem and progenitor cells. Hematologic abnormalities are prevalent in cancer patients, and many ground-breaking studies over the past decade provide insights into their underlying cellular and molecular mechanisms. Such studies demonstrate that the dysfunction of hematopoiesis is more than a side-effect of cancer pathology, but an important systemic feature of cancer disease. Here we review these many advances, covering the cancer-associated phenotypes of hematopoietic stem and progenitor cells, the dysfunction of myelopoiesis and erythropoiesis, the importance of extramedullary hematopoiesis in cancer disease, and the developmental origins of tumor associated macrophages. We address the roles of many secreted mediators, signaling pathways, and transcriptional and epigenetic mechanisms that mediate such hematopoietic dysfunction. Furthermore, we discuss the important contribution of the hematopoietic dysfunction to cancer immunosuppression, the possible avenues for therapeutic intervention, and highlight the unanswered questions and directions for future work. Overall, hematopoietic dysfunction is established as an active component of the cancer disease mechanisms and an important target for therapeutic intervention.
NF-κB-mediated anti-inflammatory effects of an organic light-emitting diode (OLED) device in lipopolysaccharide (LPS)-induced in vitro and in vivo inflammation models
Authors: Mo SangJoon , Kim Eun Young , Kwon Yi-Suk , Lee Min Young , Ahn Jin Chul
Published: December 2022

Inflammation is the body’s physiological response to harmful agents. However, if not regulated properly, inflammation can become pathological. Macrophages are key players in the inflammatory process, and modulate the immune response. Due to the side effects of anti-inflammatory drugs, non-pharmaceutical therapies for inflammatory diseases must be developed. Photobiomodulation is a non-invasive therapeutic approach to treating certain pathological conditions using light energy. Light-emitting diodes (LEDs) are commonly used as light sources for photobiomodulation treatment, but their clinical applications are limited. Organic LEDs (OLEDs) are thin, lightweight and flexible, enabling consistent and even delivery of light energy to target areas; this makes OLED promising components for therapeutic devices. In the present study, we examined the effects of OLED treatment on inflammation in vitro using a lipopolysaccharide (LPS)-induced macrophage RAW264.7 cell model, and in vivo using a pinna skin mouse model. We found that LPS-induced morphological changes and inflammatory cytokine expression were significantly reduced in RAW264.7 cells subjected to OLED treatment compared to the LPS-induced controls. This work provides evidence for the anti-inflammatory effects of OLEDs, demonstrating their potential to be incorporated into medical devices in the future.
NetTCR-2.1: Lessons and guidance on how to develop models for TCR specificity predictions
Authors: Montemurro Alessandro , Jessen Leon Eyrich , Nielsen Morten
Published: December 2022

T cell receptors (TCR) define the specificity of T cells and are responsible for their interaction with peptide antigen targets presented in complex with major histocompatibility complex (MHC) molecules. Understanding the rules underlying this interaction hence forms the foundation for our understanding of basic adaptive immunology. Over the last decade, efforts have been dedicated to developing assays for high throughput identification of peptide-specific TCRs. Based on such data, several computational methods have been proposed for predicting the TCR-pMHC interaction. The general conclusion from these studies is that the prediction of TCR interactions with MHC-peptide complexes remains highly challenging. Several reasons form the basis for this including scarcity and quality of data, and ill-defined modeling objectives imposed by the high redundancy of the available data. In this work, we propose a framework for dealing with this redundancy, allowing us to address essential questions related to the modeling of TCR specificity including the use of peptide- versus pan-specific models, how to best define negative data, and the performance impact of integrating of CDR1 and 2 loops. Further, we illustrate how and why it is strongly recommended to include simple similarity-based modeling approaches when validating an improved predictive power of machine learning models, and that such validation should include a performance evaluation as a function of “distance” to the training data, to quantify the potential for generalization of the proposed model. The conclusion of the work is that, given current data, TCR specificity is best modeled using peptide-specific approaches, integrating information from all 6 CDR loops, and with negative data constructed from a combination of true and mislabeled negatives. Comparing such machine learning models to similarity-based approaches demonstrated an increased performance gain of the former as the “distance” to the training data was increased; thus demonstrating an improved generalization ability of the machine learning-based approaches. We believe these results demonstrate that the outlined modeling framework and proposed evaluation strategy form a solid basis for investigating the modeling of TCR specificities and that adhering to such a framework will allow for faster progress within the field. The final devolved model, NetTCR-2.1, is available at https://services.healthtech.dtu.dk/service.php?NetTCR-2.1.
Monoclonal antibodies in the management of asthma: Dead ends, current status and future perspectives
Authors: Kardas Grzegorz , Panek Michał , Kuna Piotr , Damiański Piotr , Kupczyk Maciej
Published: December 2022

Patients with moderate-to-severe asthma may now be treated using a variety of monoclonal antibodies that target key inflammatory cytokines involved in disease pathogenesis. Existing clinical data on anti-IgE, anti-IL-5 and other immunological pathways indicate these therapies to offer reduced exacerbation rates, improved lung function, greater asthma control and better quality of life. However, as several patients still do not achieve satisfactory clinical response with the antibodies available, many more biologics, aiming different immunological pathways, are under evaluation. This review summarizes recent data on existing and potential monoclonal antibodies in asthma. Recent advances have resulted in the registration of a new antibody targeting TSLP (tezepelumab), with others being under development. Some of the researched monoclonal antibodies (e.g. anti-IL-13 tralokinumab and lebrikizumab or anti-IL-17A secukinumab) have shown optimistic results in preliminary research; however, these have been discontinued in asthma clinical research. In addition, as available monoclonal antibody treatments have shown little benefit among patients with T2-low asthma, research continues in this area, with several antibodies in development. This article summarizes the available pre-clinical and clinical data on new and emerging drugs for treating severe asthma, discusses discontinued treatments and outlines future directions in this area.
Remote reef cryptobenthic diversity: Integrating autonomous reef monitoring structures and in situ environmental parameters
Authors: Steyaert Margaux , Lindhart Mathilde , Khrizman Alexandra , Dunbar Robert B. , Bonsall Michael B. , Mucciarone David A. , Ransome Emma , Santodomingo Nadia , Winslade Paige , Head Catherine E. I.
Published: December 2022

Coral reef sessile organisms inhabiting cryptic spaces and cavities of the reef matrix perform vital and varied functional roles but are often understudied in comparison to those on exposed surfaces. Here, we assess the composition of cryptobenthic taxa from three remote tropical reef sites (Central Indian Ocean) alongside a suite of in situ environmental parameters to determine if, or how, significant patterns of diversity are shaped by local abiotic factors. To achieve this, we carried out a point-count analysis of autonomous reef monitoring structure (ARMS) plate images and employed in situ instrumentation to recover long-term (12 months) profiles of flow velocity, wave heights, temperature, dissolved oxygen, and salinity, and short-term (3 weeks) profiles of light and pH. We recovered distinct environmental profiles between sampling sites and observed that ocean-facing reefs experienced frequent but short-lived cooling internal wave events and that these were key in shaping in situ temperature variability. By comparing temperature and wave height profiles recovered using in situ loggers with ex situ models, we discovered that global satellite products either failed to recover site-specific profiles or both over- and underestimated actual in situ conditions. We found that site choice and recruitment plate face (top or bottom) significantly impacted the percentage cover of bryozoans, gastropods, soft and calcified tube worms, as well as crustose coralline algae (CCA) and fleshy red, brown, and green encrusting macroalgae on ARMS. We observed significant correlations between the abundance of bryozoans, CCA, and colonial tunicates with lower mean temperature and higher mean dissolved oxygen profiles observed across sites. Red and brown encrusting macroalgae abundance correlated significantly with medium-to-high flow velocities and wave height profiles, as well as higher pH and dissolved oxygen. This study provides the first insight into cryptobenthic communities in the Chagos Archipelago marine-protected area and adds to our limited understanding of tropical reef sessile communities and their associations with environmental parameters in this region. With climate change accelerating the decline of reef ecosystems, integrating analyses of cryptobenthic organisms and in situ physicochemical factors are needed to understand how reef communities, if any, may withstand the impacts of climate change.
Analysis identifying minimal governing parameters for clinically accurate in silico fractional flow reserve
Authors: Tanade Cyrus , Chen S. James , Leopold Jane A. , Randles Amanda
Published: December 2022

Background

Personalized hemodynamic models can accurately compute fractional flow reserve (FFR) from coronary angiograms and clinical measurements (FFRbaseline), but obtaining patient-specific data could be challenging and sometimes not feasible. Understanding which measurements need to be patient-tuned vs. patient-generalized would inform models with minimal inputs that could expedite data collection and simulation pipelines.

Aims

To determine the minimum set of patient-specific inputs to compute FFR using invasive measurement of FFR (FFRinvasive) as gold standard.

Materials and Methods

Personalized coronary geometries (N=50) were derived from patient coronary angiograms. A computational fluid dynamics framework, FFRbaseline, was parameterized with patient-specific inputs: coronary geometry, stenosis geometry, mean arterial pressure, cardiac output, heart rate, hematocrit, and distal pressure location. FFRbaseline was validated against FFRinvasive and used as the baseline to elucidate the impact of uncertainty on personalized inputs through global uncertainty analysis. FFRstreamlined was created by only incorporating the most sensitive inputs and FFRsemi-streamlined additionally included patient-specific distal location.

Results

FFRbaseline was validated against FFRinvasive via correlation (r=0.714, p<0.001), agreement (mean difference: 0.01±0.09), and diagnostic performance (sensitivity: 89.5%, specificity: 93.6%, PPV: 89.5%, NPV: 93.6%, AUC: 0.95). FFRsemi-streamlined provided identical diagnostic performance with FFRbaseline. Compared to FFRbaseline vs. FFRinvasive, FFRstreamlined vs. FFRinvasive had decreased correlation (r=0.64, p<0.001), improved agreement (mean difference: 0.01±0.08), and comparable diagnostic performance (sensitivity: 79.0%, specificity: 90.3%, PPV: 83.3%, NPV: 87.5%, AUC: 0.90).

Conclusion

Streamlined models could match the diagnostic performance of the baseline with a full gamut of patient-specific measurements. Capturing coronary hemodynamics depended most on accurate geometry reconstruction and cardiac output measurement.
The dynamic communities of oral microbiome in neonates
Authors: Guo Haiying , Li Jin , Yao Hantao , Liu Yina , Ji Yaoting , Zhang Jing , Zhao Yun , Du Minquan
Published: December 2022

The oral microbiome, associated with both oral disease and systemic disease, is in dynamic status along the whole life, and many factors including maternal microbiomes could impact the oral microbiome. While fewer studies have been conducted to study the characteristics of the oral microbiome in neonates and the associated maternal factors. Hence, we collected the microbiome of 15 mother-infant pairs across multiple body sites from birth up to 4 days postpartum and used high-throughput sequencing to characterize the microbiomes in mothers and their neonates. The oral microbiome in the neonates changed obviously during the 4 days after birth. Many bacteria originating from the vagina, skin, and environment disappeared in oral cavity over time, such as Prevotella bivia and Prevotella jejuni. Meanwhile, Staphylococcus epidermidis RP62A phage SP-beta, predominate bacterium in maternal skin microbiome and Streptococcus unclassified, main bacterium in vaginal microbiome, obviously increased in neonatal oral microbiome as time went on. Interestingly, as time progressed, the composition of the oral microbiome in the neonates was more similar to that of the milk microbiome in their mothers. Moreover, we found that the changes in the predominant bacteria in the neonates were in line with those in the neonates exposed to the environment. Together, these data described the sharp dynamics of the oral microbiome in neonates and the importance of maternal efforts in the development of the neonatal microbiome.
Adaptive lifestyle of bacteria determines phage-bacteria interaction
Authors: Ulrich Laura , Giez Christoph , Steiner Leon X. , Hentschel Ute , Lachnit Tim
Published: December 2022

Bacteriophages and their interactions with microbes are not well understood. As a first step toward achieving a better understanding, we isolated and sequenced the Curvibacter phage PCA1 for the purpose of eliminating Curvibacter sp. AEP1.3, the main colonizer of Hydra vulgaris AEP. Our experiments showed that PCA1 phage caused a strong, virulent infection only in sessile Curvibacter sp. AEP1.3 but was unable to infect planktonic and host-associated bacterial cells of the same strain. In an effort to investigate this phenomenon, we compared sessile, planktonic, and host-associated bacteria via RNA sequencing and found that all three states differed significantly in their expression patterns. This finding led us to propose that the adaptive lifestyle of Curvibacter sp. AEP1.3 results in varying degrees of susceptibility to bacteriophage infection. This concept could be relevant for phage research and phage therapy in particular. Finally, we were able to induce phage infection in planktonic cells and pinpoint the infection process to a membrane protein. We further identified potential phage-binding protein candidates based on expression pattern analysis.
Effects of homocysteine on nonalcoholic fatty liver related disease: A mendelian randomization study
Authors: Chen Pengcheng , Yang Ze , Guo Lingyun , Huang Yingfei , Li Jingjia , Chen Xin
Published: December 2022

Background: Since the association of homocysteine and clinical results of observational studies are controversial on non-alcoholic fatty liver related disease, we compute the two-sample Mendelian Randomization (MR) study.

Objective: To evaluate whether the plasma level of homocysteine has an effect on the risk of Non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and Cirrhosis after its progress, we investigated the causal relationships between plasma homocysteine and the three non-alcoholic fatty liver related diseases mentioned above.

Design and methods: Summary estimates were elicited from the inverse-variance weighted (IVW) method through 12 single nucleotide polymorphisms (SNPs) which related to the plasma homocysteine, the SNPs were obtained from a large genome-wide association studies (GWAS) of 44,147 European participants. And the summary statistics for the latest and largest GWAS datasets for NAFLD (307576 in total and 1,578 cases), NASH (309055 in total and 99 cases) and Cirrhosis (306145 in total and 826 cases) were collected from Ristey FinnGen website where the association of genetic variations with blood metabolite levels was conducted using comprehensive metabolite profiling. The study was performed through two-sample MR method.

Results: The result indicated that the plasma homocysteine is not significantly associated with NAFLD, and its progression, NASH and Cirrhosis.

Conclusion: The evidence in this study is quite deficient to support the causal association of the individual plasma homocysteine with NAFLD, NASH and Cirrhosis, the putative of associations is not exist.
Neuroimaging markers of dual impairment in cognition and physical performance following stroke: The Nor-COAST study
Authors: Einstad Marte Stine , Schellhorn Till , Thingstad Pernille , Lydersen Stian , Aamodt Eva Birgitte , Beyer Mona Kristiansen , Saltvedt Ingvild , Askim Torunn
Published: December 2022

Background

Cognitive decline and decline in physical performance are common after stroke. Concurrent impairments in the two domains are reported to give increased risk of dementia and functional decline. The concept of dual impairment of physical performance and cognition after stroke is poorly investigated. Clinically accessible imaging markers of stroke and pre-existing brain pathology might help identify patients at risk.

Objective

The primary aim of this study was to investigate to which extent pre-stroke cerebral pathology was associated with dual impairment in cognition and physical performance at time of stroke. Secondary aims were to examine whether white matter hyperintensities, medial temporal lobe atrophy, and stroke lesion volume and location were associated with dual impairment.

Methods

Participants from the Norwegian Cognitive Impairment After Stroke (Nor-COAST) study with available MRI data at baseline were included in this cross-sectional study. Logistic regression analyses were conducted, with impairment status (no impairment, impaired cognition, impaired physical performance, and dual impairment) as the dependent variable and MRI markers as covariates. Pre-existing brain pathologies were classified into neurodegenerative, cerebrovascular, or mixed pathology. In addition, white matter hyperintensities and medial temporal lobe atrophy were included as independent covariates. Stroke volume and location were also ascertained from study-specific MRI scans.

Results

Participants’ (n = 348) mean (SD) age was 72.3 (11.3) years; 148 (42.5%) were women. Participants with dual impairment (n = 99) were significantly older, had experienced a more severe stroke, and had a higher comorbidity burden and poorer pre-stroke function. Stroke lesion volume (odds ratio 1.03, 95%, confidence interval 1.00 to 1.05, p = 0.035), but not stroke location or pre-existing brain pathology, was associated with dual impairment, after adjusting for age and sex.

Conclusion

In this large cohort of stroke survivors having suffered mainly mild to moderate stroke, stroke lesion volume—but not pre-existing brain pathology—was associated with dual impairment early after stroke, confirming the role of stroke severity in functional decline.
Systematic review of Kaixinsan in treating depression: Efficacy and pharmacological mechanisms
Authors: Bo Menghan , Zhang Hongjing , Xu Jia , Zhao Hong , Jia Xinglei , Wang Guangdong , Lu Zhengyu
Published: December 2022

Introduction

Kaixinsan (KXS) has been in use as an effective classic formulation of traditional Chinese medicine for depression. However, its active components and action mechanism against depression remain elusive. The purpose of this study was to summarize and evaluate the efficacy and potential pharmacological mechanisms of KXS in antidepressant treatment.

Materials and methods

Reports on the use of KXS in the treatment of depression were systematically collected from PubMed, Web of Science, Embase, China National Knowledge Infrastructure, Chongqing VIP, and Wanfang Data from the establishment to July 2022, including those on mood disorders in neurological diseases such as Alzheimer’s disease. Meta-analysis was conducted with the Review Manager 5.3 software. Online datasets, traditional Chinese medicine system pharmacological analysis platform, GeneCards, online Mendelian inheritance in man, and DisGeNET were used to investigate the depression-related genes. The gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichments were performed to construct the ‘component-target-pathways’ network using Metascape online analyses.

Result

Ten studies were included in the analysis. Meta-analysis showed that both low-dose KXS (SMD = 19.66, Z = 7.96, and I2 = 42%) and high-dose KXS (SMD = 23.84, Z = 8.46, and I2 = 13%) could increase the sucrose preference in depression models. In addition, 5-hydroxytryptamine (5-HT) (SMD = 10.91, Z = 2.95, and I2 = 50%) returned to normal level after the treatment at low dose KXS. In network pharmacology, 50 active components and 376 gene targets were screened out. AKT1, GAPDH, ALB, TNF, and TP53 were the core target proteins. GO analysis showed that KXS mainly treats depression in biological processes such as response to drugs, cellular calcium ion homeostasis, and regulation of chemical synaptic signal transmission. KEGG results show that the mechanism of action of KXS in treating depression is through neural activity ligand-receptor interaction, the calcium signaling and CAMP signaling pathways.

Discussion

The study reveals the active components and potential molecular mechanism of KXS in the treatment of depression and provides evidence for future basic research.