Primary Function Research Articles

Sumatera Utara Botanical Conservatory (With Ecology Architecture Design Approach)

Climate change affects many things, especially plant diversity. Indonesia's number of endangered plant species continues to increase every year. Meanwhile, ex-situ conservation and research facilities are still unavailable in North Sumatra. The conservatory itself has the primary function as a conservation institution that seeks to maintain and breed various types of plants, especially endangered plants, used to protect and preserve nature, education facilities, development of science and technology, and recreation. The research was conducted using the descriptive-analytic method by drawing problems regarding the concept of conservatory design that pays attention to the environment while collecting data and theories related to the conservatory. The conservatory applies an ecological architectural approach that includes harmony between humans and nature; the balance of development between the natural environment and buildings that need to be considered will become a sustainable green building. This project is expected to create a medium for conservation and research beneficial to the community, as educational and interactive tourism facilities between humans and nature that are sustainable and have no negative impact on the environment.

A four-part guide to lung immunology: Invasion, inflammation, immunity, and intervention.

Lungs are important respiratory organs primarily involved in gas exchange. Lungs interact directly with the environment and their primary function is affected by several inflammatory responses caused by allergens, inflammatory mediators, and pathogens, eventually leading to disease. The immune architecture of the lung consists of an extensive network of innate immune cells, which induce adaptive immune responses based on the nature of the pathogen(s). The balance of immune responses is critical for maintaining immune homeostasis in the lung. Infection by pathogens and physical or genetic dysregulation of immune homeostasis result in inflammatory diseases. These responses culminate in the production of a plethora of cytokines such as TSLP, IL-9, IL-25, and IL-33, which have been implicated in the pathogenesis of several inflammatory and autoimmune diseases. Shifting the balance of Th1, Th2, Th9, and Th17 responses have been the targets of therapeutic interventions in the treatment of these diseases. Here, we have briefly reviewed the innate and adaptive i3mmune responses in the lung. Genetic and environmental factors, and infection are the major causes of dysregulation of various functions of the lung. We have elaborated on the impact of inflammatory and infectious diseases, advances in therapies, and drug delivery devices on this critical organ. Finally, we have provided a comprehensive compilation of different inflammatory and infectious diseases of the lungs and commented on the pros and cons of different inhalation devices for the management of lung diseases. The review is intended to provide a summary of the immunology of the lung, with an emphasis on drug and device development.

Intrinsically Disordered Kiwellin Protein-Like Effectors Target Plant Chloroplasts and are Extensively Present in Rust Fungi.

The effector proteins produced by plant pathogens are one of the essential components of host-pathogen interaction. Despite being important, most of the effector proteins remain unexplored due to the diversity in their primary sequence generated by the high selection pressure of the host immune system. However to maintain the primary function in the infection process, these effectors may tend to maintain their native protein fold to perform the corresponding biological function. In the present study, unannotated candidate secretory effector proteins of sixteen major plant fungal pathogens were analyzed to find the conserved known protein folds using homology, ab initio, and AlphaFold/Rosetta Foldprotein dimensional (3D) structure approaches. Several unannotated candidate effector proteins were found to match various known conserved protein families potentially involved in host defense manipulation in different plant pathogens. Surprisingly a large number of plant Kiwellin proteins fold like secretory proteins (> 100) were found in studied rust fungal pathogens. Many of them were predicted as potential effector proteins. Furthermore, template independent modelling usingAlphaFold/Rosetta Fold analysis and structural comparison of these candidates also predicted them to match with plant Kiwellin proteins. We also found plant Kiwellin matching proteinsoutside rusts including several non-pathogenic fungi suggesting the broad function of these proteins. One of the highest confidently modeled Kiwellin matching candidates effectors, Pstr_13960 (97.8%), from the Indian P. striiformis race Yr9 was characterized using overexpression, localization, and deletion studies in Nicotiana benthamiana. The Pstr_13960 suppressed the BAX-induced cell death and localized in the chloroplast. Furthermore, the expression of the Kiwellin matching region (Pst_13960_kiwi) alone suppressed the BAX-induced cell death in N. benthamiana despite the change of location to the cytoplasm and nucleus, suggesting the novel function of the Kiwellin corefold in rust fungi. Molecular docking showed that Pstr_13960 can interact with plant Chorismate mutases (CMs) using three loops conserved in plant and rust Kiwellins. Further analysis of Pstr_13960 showed to contain Intrinsically disordered regions (IDRs) in place of the N-terminal β1/β2 region found in plant Kiwellins suggesting the evolution of rust Kiwellins-like effectors (KLEs). Overall, this study reports the presence of a Kiwellin protein-like fold containing a novel effector protein family in rust fungi depicting a classical example of the evolution of effectors at the structure level as Kiwellin effectors show very low significant similarity to plant Kiwellin at the sequence level.

Fruit secondary metabolites alter the quantity and quality of a seed dispersal mutualism.

Plant secondary metabolites are key mechanistic drivers of species interactions. These metabolites have primarily been studied for their role in defense, but they can also have important consequences for mutualisms, including seed dispersal. Although the primary function of fleshy fruits is to attract seed-dispersing animals, fruits often contain complex mixtures of toxic or deterrent secondary metabolites that can reduce the quantity or quality of seed dispersal mutualisms. Furthermore, because seeds are often dispersed across multiple stages by several dispersers, the net consequences of fruit secondary metabolites for the effectiveness of seed dispersal and ultimately plant fitness are poorly understood. Here, we tested the effects of amides, nitrogen-based defensive compounds common in fruits of the neotropical plant genus Piper (Piperaceae), on seed dispersal effectiveness (SDE) by ants, which are common secondary seed dispersers. We experimentally added amide extracts to Piper fruits both in the field and lab, finding that amides reduced the quantity of secondary seed dispersal by reducing ant recruitment (87%) and fruit removal rates (58% and 66% in the field and lab, respectively). Moreover, amides not only reduced dispersal quantity but also altered seed dispersal quality by shifting the community composition of recruiting ants (notably by reducing the recruitment of the most effective disperser by 90% but having no detectable effect on the recruitment of a cheater species that removes fruit pulp without dispersing seeds). Although amides did not affect the distance ants initially carried seeds, they altered the quality of seed dispersal by reducing the likelihood of ants cleaning seeds (67%) and increasing their likelihood of ants redispersing seeds outside of the nest (200%). Overall, these results demonstrate that secondary metabolites can alter the effectiveness of plant mutualisms, by both reducing mutualism quantity and altering mutualism quality through multiple mechanisms. These findings present a critical step in understanding the factors mediating the outcomes of seed dispersal and, more broadly, demonstrate the importance of considering how defensive secondary metabolites influence the outcomes of mutualisms surrounding plants.

Proteins in pregnant swine serum promote the African swine fever virus replication: an iTRAQ-based quantitative proteomic analysis

African swine fever (ASF) is a severe infectious disease caused by the African swine fever virus (ASFV), seriously endangering the global pig industry. ASFV possesses a large genome, strong mutation ability, and complex immune escape mechanisms. Since the first case of ASF was reported in China in August 2018, it has had a significant impact on social economy and food safety. In the present study, pregnant swine serum (PSS) was found to promote viral replication; differentially expressed proteins (DEPs) in PSS were screened and identified using the isobaric tags for relative and absolute quantitation technology and compared with those in non-pregnant swine serum (NPSS). The DEPs were analyzed using Gene Ontology functional annotation, Kyoto Protocol Encyclopedia of Genes and Genome pathway enrichment, and protein–protein interaction networks. In addition, the DEPs were validated via western blot and RT-qPCR experiments. And the 342 of DEPs were identified in bone marrow-derived macrophages cultured with PSS compared with the NPSS. The 256 were upregulated and 86 of DEPs were downregulated. The primary biological functions of these DEPs involved signaling pathways that regulate cellular immune responses, growth cycles, and metabolism-related pathways. An overexpression experiment showed that the PCNA could promote ASFV replication whereas MASP1 and BST2 could inhibit it. These results further indicated that some protein molecules in PSS were involved in the regulation of ASFV replication. In the present study, the role of PSS in ASFV replication was analyzed using proteomics, and the study will be provided a basis for future detailed research on the pathogenic mechanism and host interactions of ASFV as well as new insights for the development of small-molecule compounds to inhibit ASFV.

Molecular Determinants of Mouse Adaptation of Rat Hepacivirus.

The lack of robust immunocompetent animal models for hepatitis C virus (HCV) impedes vaccine development and studies of immune responses. Norway rat hepacivirus (NrHV) infection in rats shares HCV-defining characteristics, including hepatotropism, chronicity, immune responses, and aspects of liver pathology. To exploit genetic variants and research tools, we previously adapted NrHV to prolonged infection in laboratory mice. Through intrahepatic RNA inoculation of molecular clones of the identified variants, we here characterized four mutations in the envelope proteins responsible for mouse adaptation, including one disrupting a glycosylation site. These mutations led to high-titer viremia, similar to that observed in rats. In 4-week-old mice, infection was cleared after around 5 weeks compared to 2 to 3 weeks for nonadapted virus. In contrast, the mutations led to persistent but attenuated infection in rats, and they partially reverted, accompanied by an increase in viremia. Attenuated infection in rat but not mouse hepatoma cells demonstrated that the characterized mutations were indeed mouse adaptive rather than generally adaptive across species and that species determinants and not immune interactions were responsible for attenuation in rats. Unlike persistent NrHV infection in rats, acute resolving infection in mice was not associated with the development of neutralizing antibodies. Finally, infection of scavenger receptor B-I (SR-BI) knockout mice suggested that adaptation to mouse SR-BI was not a primary function of the identified mutations. Rather, the virus may have adapted to lower dependency on SR-BI, thereby potentially surpassing species-specific differences. In conclusion, we identified specific determinants of NrHV mouse adaptation, suggesting species-specific interactions during entry. IMPORTANCE A prophylactic vaccine is required to achieve the World Health Organization's objective for hepatitis C virus elimination as a serious public health threat. However, the lack of robust immunocompetent animal models supporting hepatitis C virus infection impedes vaccine development as well as studies of immune responses and viral evasion. Hepatitis C virus-related hepaciviruses were discovered in a number of animal species and provide useful surrogate infection models. Norway rat hepacivirus is of particular interest, as it enables studies in rats, an immunocompetent and widely used small laboratory animal model. Its adaptation to robust infection also in laboratory mice provides access to a broader set of mouse genetic lines and comprehensive research tools. The presented mouse-adapted infectious clones will be of utility for reverse genetic studies, and the Norway rat hepacivirus mouse model will facilitate studies of hepacivirus infection for in-depth characterization of virus-host interactions, immune responses, and liver pathology.

Development of a protocol to identify land function based on multifunctionality and suitability analysis: A case study of the Nanyuntai Forest Farm, China

Accurately identifying regional land functions is important for balancing and coordinating multiple ecosystem services. Identification of land functions should be guided by the ecological suitability analysis framework, highlighting the primary ecological function and considering the temporal and spatial trends of land functions to resolve the contradictions among various needs of land ecology, production, and life. Taking Nanyuntai Forest Farm in Lianyungang City, Jiangsu Province, as a case study, we used the Analytical Hierarchical Process to construct a systematic and complete land multi-function evaluation and spatial suitability evaluation system, and used the ArcGIS spatial analysis technology to analyze its land function changes from 2011 to 2021. Finally, the results of multifunctionality and suitability analysis were integrated to identify the land's ecological, production, and living functions by constructing the algorithm using Python. Our results showed that the proportions of ecological, production, and living functions of the land in the study area were 56.82, 34.03, and 9.15%, respectively. This study highlighted that the results of land function identification based on comprehensive land-change-trend and spatial suitability analyses were more precise and coordinated. This comprehensive evaluation is a valuable and practical method for decision-makers and land managers to create land use maps and determine high-priority areas that require conservation measures for sustainable management. Moreover, this approach can be practically applied to other planning units.

Identification of Dp140 and α1-syntrophin as novel molecular interactors of the neuronal CaV2.1 channel.

The primary function of dystrophin is to form a link between the cytoskeleton and the extracellular matrix. In addition to this crucial structural function, dystrophin also plays an essential role in clustering and organizing several signaling proteins, including ion channels. Proteomic analysis of the whole rodent brain has stressed the role of some components of the dystrophin-associated glycoprotein complex (DGC) as potential interacting proteins of the voltage-gated Ca2+ channels of the CaV2 subfamily. The interaction of CaV2 with signaling and scaffolding proteins, such as the DGC components, may influence their function, stability, and location in neurons. This work aims to study the interaction between dystrophin and CaV2.1. Our immunoprecipitation data showed the presence of a complex formed by CaV2.1, CaVα2δ-1, CaVβ4e, Dp140, and α1-syntrophin in the brain. Furthermore, proximity ligation assays (PLA) showed that CaV2.1 and CaVα2δ-1 interact with dystrophin in the hippocampus and cerebellum. Notably, Dp140 and α1-syntrophin increase CaV2.1 protein stability, half-life, permanence in the plasma membrane, and current density through recombinant CaV2.1 channels. Therefore, we have identified the Dp140 and α1-syntrophin as novel interaction partners of CaV2.1 channels in the mammalian brain. Consistent with previous findings, our work provides evidence of the role of DGC in anchoring and clustering CaV channels in a macromolecular complex.

UBQLN2 restrains the domesticated retrotransposon PEG10 to maintain neuronal health in ALS.

Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive motor neuron dysfunction and loss. A portion of ALS cases are caused by mutation of the proteasome shuttle factor Ubiquilin 2 (UBQLN2), but the molecular pathway leading from UBQLN2 dysfunction to disease remains unclear. Here, we demonstrate that UBQLN2 regulates the domesticated gag-pol retrotransposon 'paternally expressed gene 10 (PEG10)' in human cells and tissues. In cells, the PEG10 gag-pol protein cleaves itself in a mechanism reminiscent of retrotransposon self-processing to generate a liberated 'nucleocapsid' fragment, which uniquely localizes to the nucleus and changes the expression of genes involved in axon remodeling. In spinal cord tissue from ALS patients, PEG10 gag-pol is elevated compared to healthy controls. These findings implicate the retrotransposon-like activity of PEG10 as a contributing mechanism in ALS through the regulation of gene expression, and restraint of PEG10 as a primary function of UBQLN2.

Does Monocyte Chemoattractant Protein-1 Levels Determine the Prognosis of Covid-19 Disease in Kidney Transplant Recipients?

In the normal population, a high monocyte chemoattractant protein (MCP-1) level is an important biomarker for the progression of COVID-19. This study investigated whether MCP-1 level can determine the disease prognosis in kidney transplant (KT) patients with COVID-19. A total of 89 patients, including 49 KT patients (group 1) diagnosed with COVID-19 who required hospitalization, and 40 KT patients who did not have COVID-19 disease (group 2), were included. Demographic characteristics and laboratory results of the patients were recorded. The serum reserved for MCP-1 was stored at -80°C and studied blindly by a single microbiologist at the end of the study. While the mean age of the patients was 51.0 years (40.0-59.50) in group 1, it was 48.0 years (40.75-54.75) in group 2 (P > .05). In terms of the female sex, it was 36 (73.5%) and 27 (67.5%) in group 1 and group 2, respectively (P > .05). Similarly, there was no significant difference between the 2 groups regarding primary disease and basal graft function (P > .05). There was a statistically significant difference in inflammation indicators in group 1 compared with group 2 (P < .05). A correlation was found between inflammation indicators and COVID-19 (P < .05). However, no significant correlation was detected between COVID-19 disease and MCP-1 levels in both groups (P > .05). Also, according to basal MCP-1 levels, we did not find a significant difference between survival and nonsurvival patients (164.0 pg/mL [146.0-202.0] vs 156.0 pg/mL [143.0-173.0], respectively (P > .05). Monocyte chemoattractant protein, an indicator of inflammation, was not found to predict the prognosis of COVID-19 disease in kidney recipients.

Early Postoperative Volume Overload is a Predictor of 1-Year Post-Transplant Mortality in Pediatric Heart Transplant Recipients

Fluid restriction and diuretic management are mainstays in the postoperative management of cardiac patients, at risk of volume overload and its deleterious effects on primary cardiac function and multi-organ systems. The importance of fluid homeostasis is further emphasized among orthotopic heart transplant recipients (OHT). We sought to investigate the relationship between postoperative volume overload, mortality, and allograft dysfunction among pediatric OHT recipients within 1-year of transplantation. This is a retrospective cohort study from a single pediatric OHT center. Children under 21 years undergoing cardiac transplantation between 2010 and 2018 were included. Cumulative fluid overload (cFO) was assessed as percent fluid accumulation adjusted for preoperative body weight. Greater than 10% cFO defined those with postoperative cFO and a comparison of postoperative cFO vs. no postoperative cFO (< 5%) is reported. 102 pediatric OHT recipients were included. Early cFO at 72 h post-OHT occurred in 14% and overall cFO at 1-week post-OHT occurred in 23% of patients. Risk factors for cFO included younger age, lower weight, and postoperative ECMO. Early cFO was associated with postoperative mortality at 1-year, OR 8.6 (95% CI 1.4, 51.6), p = 0.04, independent of age and weight. There was no significant relationship between cFO and allograft dysfunction, measured by rates of clinical rejection and cardiopulmonary filling pressures within 1-year of transplant. Early postoperative volume overload is prevalent and associated with increased risk of death at 1-year among pediatric OHT recipients. It may be an important postoperative marker of transplant survival, and this relationship warrants further clinical investigation.

Determination of workers' compliance to safety regulations using a spatio-temporal graph convolution network

The safety of workers in construction remains a critical issue despite the automation of several tasks with fewer workers on site. As fatal accidents of workers account for a significant number of construction accidents, considerable effort has been made to monitor workers’ safety behaviors with additional personnel for supervising workers. With the advancement of data analytics, recent research has reported various human activity recognition methods based on image data to perform automated worker monitoring without additional labor. Nevertheless, unlike existing approaches based on a single image, a method that can capture a series of actions from sequential images is required to monitor workers’ compliance with safety behavior. To this end, an approach based on OpenPose and a spatio-temporal graph convolutional network is proposed in this study to evaluate workers’ compliance with safety regulations using sequential videos. The two primary functions of the developed method include 1) classifying each safety behavior among five representative behaviors stipulated in construction, and 2) determining the compliance of workers with each safety regulation. The results indicate that the developed approach can capture momentary safety behaviors and workers’ compliance with feasible accuracy of an average F1 score greater than 0.8. Furthermore, the proposed method can be extended to safety intervention policies with behavior-based feedback to inform workers of their non-compliance with safety behaviors. Therefore, this study contributes to proactive safety management by focusing on workers’ behavioral levels rather than on accident rate-based management.

Connecting the right knots: The impact of board committee interlocks on the performance of Indian firms

AbstractResearch Question/IssueInformation processing, agency, and resource dependence perspectives provide diverging predictions regarding the relationship between board interlocks and firm performance, which are rooted in different perspectives on the roles of boards of directors. This study argues that these various approaches are reconcilable when considering the nature of board committees to which the interlocked directors are assigned.Research Findings/InsightsWe test our hypotheses on a sample of 5133 firm‐year observations in India. Our analyses support our hypotheses. The results show that interlocks between audit committees, whose primary function relates to providing financial oversight and ensuring compliance, are negatively related to firm performance. In contrast, interlocks between nomination and remuneration committees of Indian firms, which provide them with access to resources such as human capital and information on appropriate incentive structures, are positively related to performance.Theoretical/Academic ImplicationsOur study clarifies the relationship between board committee interlocks and firm performance by taking a multi‐theoretical perspective. Our analysis suggests that information processing, agency, and resource dependence theories complement one another in explaining the effect of interlocks on firm performance.Practitioner/Policy ImplicationsOur results show that it is not board interlocks per se that are detrimental to firm performance; in fact, appointing well‐connected directors with experience in serving on other boards might be beneficial for firms. However, firms should not assign specific monitoring‐intensive tasks such as auditing to directors who also serve on other firms' audit committees. Our findings suggest that these directors should have greater independence and focus.

Enantioselective Synthesis of [b]‐Annulated Azepane Scaffolds

AbstractCyclopenta‐, benzo‐, and cyclohepta[b]‐annulated azepane scaffolds were prepared in two steps from optically active cyclic α‐allyl‐β‐oxoesters. The first step was ruthenium‐catalyzed olefin cross metathesis with acrylonitrile. The second step was palladium‐catalyzed dihydrogenation which consists of three consecutive processes: The hydrogenation of the C−C double and C−N triple bonds was followed by the reductive amination via the iminium ion formed in situ from the primary amino function and the endocyclic carbonyl group. This last step gave, stereoselectively, the annulated azepanes with relative trans‐configuration. The amino function and the ester group define two points for further diversification of the scaffolds. The trifluoroacetyl derivatives allowed to establish the enantiopurity of the products to be 97–98 % ee by GLC on a chiral phase. The relative trans‐configurations and in one case also the absolute (R,R)‐configuration was established by X‐ray crystallography.

Influence of the In-Cylinder Catalyst on the Aftertreatment Efficiency of a Diesel Engine

The article discusses the use of a catalyst inside the cylinder, the task of which is to reduce exhaust emissions from a diesel engine. The catalyst (platinum) applied to the glow plugs provided an additional method of exhaust aftertreatment. Due to their usage, especially in urban driving, passenger cars are characterized by small mileage between individual trips, so they often operate from a cold engine start and work at a low engine temperature, which leads to reduced catalytic reactor efficiency. For this reason, the efficiency of the internal catalyst was tested in relation to the efficiency of the external reactor. This efficiency was determined based on exhaust emission measurements (before and after the catalytic reactor) in two stages: stage 1: idling of a hot engine, and stage 2: simulation of the NEDC test (valid for the selected test object). The tests were carried out on an engine dynamometer, where the traffic conditions from the type-approval test carried out on a chassis dynamometer could be replicated. The tests were carried out on a Euro 4 1.3 JTD MultiJet diesel engine. The results (measurement of carbon monoxide, hydrocarbons, and the number of particles) related to the assessment of the effect the catalyst in the cylinder were discussed. The obtained catalytic reactor efficiency results, regardless of the type of research, indicated that it achieved the highest efficiency in reducing the concentration of hydrocarbons, and the lowest—in relation to the number of solid particles (as that is not its primary function). It is particularly significant that the in-cylinder catalytic converter was most efficient during the cold engine start, which happens frequently in urban driving. The efficiency of the diesel oxidation catalytic reactor (DOC) during the engine start-up and warm-up phases with the use of standard glow plugs reached values of 31.3%, 34.1% and 14.3%, respectively, for carbon monoxide, hydrocarbons and the particle number. On the other hand, the determined efficiency of the DOC in a setup with the modified glow plugs was 28.9%, 35.7% and 12.5%, respectively. The proposed solution can be used to improve the combustion quality in internal combustion engines used in hybrid vehicles, which are characterized by frequent engine starts and stops. In addition, it is possible to use such a solution retroactively in traditional vehicles powered by an internal combustion engine, which could result in an improvement in their emission class through what is called retrofitting.

Unveiling the Language Techniques Behind the Pragmatic Meaning of Sarcasm in American Confrontational Film Discourse

This article delves into the concept of sarcasm in confrontational American film discourse, examining its primary functions and characteristics. Specifically, the study focuses on how sarcastic statements are used in American television series to heighten emotional engagement and aesthetic appeal. The defining features of sarcasm, namely implicitness and double meaning, are also discussed. The analysis is conducted through a case study of the modern American drama series “This is Us”, which highlights the key mechanisms utilized to achieve the pragmatic effect of sarcasm, including intonation, metaphors, and repetitions. Additionally, the article examines the work of translators, their professional challenges, and the methods and techniques employed to convey the semantic content of sarcastic messages in the target language. The findings suggest that translational means such as literal translation, ellipses, and equivalent translation are effective in transferring the intended sarcasm across languages. Overall, this study provides insight into the language techniques and translational strategies involved in the implementation of sarcasm in confrontational American film discourse.

Control of myeloid cell functions by nociceptors.

The immune system has evolved to protect the host from infectious agents, parasites, and tumor growth, and to ensure the maintenance of homeostasis. Similarly, the primary function of the somatosensory branch of the peripheral nervous system is to collect and interpret sensory information about the environment, allowing the organism to react to or avoid situations that could otherwise have deleterious effects. Consequently, a teleological argument can be made that it is of advantage for the two systems to cooperate and form an "integrated defense system" that benefits from the unique strengths of both subsystems. Indeed, nociceptors, sensory neurons that detect noxious stimuli and elicit the sensation of pain or itch, exhibit potent immunomodulatory capabilities. Depending on the context and the cellular identity of their communication partners, nociceptors can play both pro- or anti-inflammatory roles, promote tissue repair or aggravate inflammatory damage, improve resistance to pathogens or impair their clearance. In light of such variability, it is not surprising that the full extent of interactions between nociceptors and the immune system remains to be established. Nonetheless, the field of peripheral neuroimmunology is advancing at a rapid pace, and general rules that appear to govern the outcomes of such neuroimmune interactions are beginning to emerge. Thus, in this review, we summarize our current understanding of the interaction between nociceptors and, specifically, the myeloid cells of the innate immune system, while pointing out some of the outstanding questions and unresolved controversies in the field. We focus on such interactions within the densely innervated barrier tissues, which can serve as points of entry for infectious agents and, where known, highlight the molecular mechanisms underlying these interactions.

RNA Editing Enzyme ADAR1 Suppresses the Mobility of Cancer Cells via ARPIN.

Deamination of adenine or cytosine in RNA, called RNA editing, is a constitutively active and common modification. The primary role of RNA editing is tagging RNA right after its synthesis so that the endogenous RNA is recognized as self and distinguished from exogenous RNA, such as viral RNA. In addition to this primary function, the direct or indirect effects on gene expression can be utilized in cancer where a high level of RNA editing activity persists. This report identified actin-related protein 2/3 complex inhibitor (ARPIN) as a target of ADAR1 in breast cancer cells. Our comparative RNA sequencing analysis in MCF7 cells revealed that the expression of ARPIN was decreased upon ADAR1 depletion with altered editing on its 3'UTR. However, the expression changes of ARPIN were not dependent on 3'UTR editing but relied on three microRNAs acting on ARPIN. As a result, we found that the migration and invasion of cancer cells were profoundly increased by ADAR1 depletion, and this cellular phenotype was reversed by the exogenous ARPIN expression. Altogether, our data suggest that ADAR1 suppresses breast cancer cell mobility via the upregulation of ARPIN.

Molecular HLA mismatching for prediction of primary humoral alloimmunity and graft function deterioration in paediatric kidney transplantation.

Rejection remains the main cause of allograft failure in paediatric kidney transplantation and is driven by donor-recipient HLA mismatching. Modern computational algorithms enable assessment of HLA mismatch immunogenicity at the molecular level (molecular-mismatch, molMM). Whilst molMM has been shown to correlate with alloimmune outcomes, evidence demonstrating improved prediction performance against traditional antigen mismatching (antMM) is lacking. We analysed 177 patients from the CERTAIN registry (median follow-up 4.5 years). molMM scores included Amino-Acid-Mismatch-Score (AAMS), Electrostatic-Mismatch-Score (EMS3D) and netMHCIIpan (netMHC1k: peptide binding affinity ≤1000 nM; netMHC: binding affinity ≤500 nM plus rank <2%). We stratified patients into high/low-risk groups based on risk models of DSA development. Donor-specific HLA antibodies (DSA) predominantly targeted the highest scoring molMM donor antigen within each HLA locus. MolMM scores offered superior discrimination versus antMM in predicting de novo DSA for all HLA loci; the EMS3D algorithm had particularly consistent performance (area under the receiver operating characteristic curve (AUC) >0.7 for all HLA loci vs. 0.52-0.70 for antMM). ABMR (but not TCMR) was associated with HLA-DQ molMM scores (AAMS, EMS3D and netMHC). Patients with high-risk HLA-DQ molMM had increased risk of graft function deterioration (50% reduction in baseline eGFR (eGFR50), adjusted HR: 3.5, 95% CI 1.6-8.2 high vs. low EMS3D). Multivariable modelling of the eGFR50 outcome using EMS3D HLA-DQ stratification showed better discrimination (AUC EMS3D vs. antMM at 2 years: 0.81 vs. 0.77, at 4.5 years: 0.72 vs. 0.64) and stratified more patients into the low-risk group, compared to traditional antMM. Molecular mismatching was superior to antigen mismatching in predicting humoral alloimmunity. Molecular HLA-DQ mismatching appears to be a significant prognostic factor for graft function deterioration in paediatric kidney transplantation.

Nanoparticles that Transcytosed through Cancer Cells Can Elicit Immune Response.

Transcytosis is a crucial process that nanomedicines can experience in various delivery stages. However, little was known about whether it endows biofunctions to the nanomedicines. Here, we reported that transporting photodynamic nanoparticles across cancer cells via the endoplasmic reticulum (ER)-Golgi pathway formulated them with abundant neoantigens and damage-associated molecular patterns. The resultant nanoparticles (Tran-NPs) were potent in dendritic cell maturation and T cell activation. Meanwhile, the photodynamic Tran-NPs maintained their primary function of repolarizing immunosuppressive cells. The immune responses were observed in melanoma B16F10 tumor models. Our work suggested that the transcytosis process reprogrammed the nanoparticles with immunological properties, which might shed light on the design of nanomedicines.