bluuebunny/crossref_metadata_2025 huggingface dataset:
Digital Signature System Using SHA-3 and ECDSA
Authors: Ismail Ade , F Vipkas Al Hadid , F Anissa Taufika
Published: October 2023

This research aims to implement an information security system for electronic documents using electronic signatures based on  ECDSA (Elliptic Curve Digital Signature Algorithm) and SHA-3 (Secure Hash Algorithm 3) algorithms. This research was conducted to answer questions about the security and integrity protection of digital documents in today's digital age. The research method used is a randomized controlled experiment testing the effectiveness of a security system implemented in a simulated environment. The data obtained from this experiment were statistically analyzed with valid and reliable results. Research results  show that implementing a security system with digital signatures based on ECDSA and SHA-3 effectively protects the security and integrity of digital documents. The ECDSA algorithm ensures the legitimacy and authentication of digital documents through a digital signature process using private and public keys. The SHA-3 algorithm is used as a strong hashing algorithm to compute hashes of digital documents to ensure data integrity. The results show that a security system implemented using digital signatures based on ECDSA and SHA-3 can provide a high level of security in protecting digital documents. Prevent unauthorized changes and tampering.
Analisis Overall Equipment Effectiveness untuk Meningkatkan Efektivitas Mesin Filling Multiline pada PT-XYZ
Authors: Rafi Fahmi Abdul , Wahyudin Wahyudin , Nugraha Billy
Published: October 2023

Dalam era industri modern, efektivitas operasional menjadi fokus utama bagi perusahaan manufaktur. PT-XYZ, sebuah perusahaan terkemuka dalam produksi bumbu masak, menghadapi tantangan dalam meningkatkan efektivitas mesin filling multiline mereka. PT XYZ merupakan perusahaan penyedap bumbu makanan yang menggunakan mesin mixer dan mesin filling. Pada mesin filling multiline dari hasil penelitian menunjukkan adanya masalah downtime yang tinggi, kecepatan produksi yang tidak optimal, dan tingkat cacat produk yang melebihi batas toleransi. Penelitian ini bertujuan untuk menganalisis perhitungan Overall Equipment Effectiveness (OEE) pada mesin filling multiline di PT XYZ dengan tujuan meningkatkan efektivitasnya. Metode penelitian melibatkan pengumpulan data ketersediaan mesin, kinerja mesin, dan kualitas produk yang dihasilkan oleh mesin filling multiline. Data tersebut dianalisis menggunakan perhitungan OEE dan dilakukan identifikasi penyebab utama rendahnya efektivitas mesin dengan menerapkan OEE dan analisis Six Big Losses, penelitian ini bertujuan membantu PT-XYZ meningkatkan produktivitas mesin dan mencapai target MSA (Master Schedule Attainment) produksi yang ditetapkan. Rekomendasi perbaikan yang disarankan meliputi perawatan rutin yang lebih intensif, serta peningkatan kontrol kualitas. Diharapkan implementasi perbaikan ini dapat meningkatkan OEE mesin filling multiline dan efektivitas produksi secara keseluruhan di PT XYZ
Western Power Relations Against the East in the Code Geass Anime Series
Authors: Wijaya Michael Janshen , Puspitasari Diana , Suryadi Yudi
Published: October 2023

The aim of the research is to identify four power relations of the West over the East in the anime series Code Geass: Lelouch of the Rebellion by using postcolonial studies, namely Edward Said's concept of Orientalism. This type of research is qualitative descriptive research. This study used observing and note-taking techniques in the data collection process. Data analysis in this study consisted of data reduction, data presentation, and drawing conclusions. The results of this study indicate that the four power relations of the West over the East are present in the form of British power over Japan. The first is political power, shown by Britannia as the ruler of Japan. Second, intellectual power is demonstrated by the influence of the Britannia media in portraying Eleven in a bad image. The three cultural powers, shown by the influence of Britannia positioned themselves as a party capable of modernizing Japan. The four moral powers are demonstrated by the form of criticism of a Prince of Britannia who saw the resistance carried out by the Japanese. The conclusion is the influence of the most incredible power is political power through Britannia which affects the lives of Japanese people in New Japan/Area 11.
ÜRÜN ÇEŞİTLİLİĞİNİN GÜCÜ: ÇOK FAZLA SEÇENEK MÜŞTERİ DENEYİMİNİ NASIL ETKİLER?
Authors: YILDIZ Selçuk Yasin
Published: October 2023

Online alışverişin yükselişi, tüketicilerin mal ve hizmet satın alma yöntemlerinde büyük değişimlere yol açmıştır. E-ticaret platformlarının çoğalması ve parmaklarımızın ucunda sürekli genişleyen geniş ürün yelpazesi ile tüketicilere daha önce hiç olmadığı kadar geniş ve çeşitli bir pazar sunulmaktadır. Online olarak sunulan çeşitli ürün kategorileri arasında, hazır giyim pazarı en dinamik ve etkili sektörlerden biri olarak öne çıkmaktadır. Hazır giyim sektörü, geniş stil, beden ve tasarım çeşitliliğiyle online alışverişi tüketiciler için giderek daha cazip hale getirmiştir. Sonuç olarak, çevrimiçi alışveriş platformları, farklı tercihlere sahip daha geniş bir kitleye hitap etmek için ürün tekliflerini genişletmeyi amaçlamaktadır. Bu genişleme önemli bir soruyu gündeme getirmiştir: Online hazır giyim alışverişinde mevcut olan geniş ürün çeşitliliği müşteri memnuniyetini ve sadakat niyetlerini nasıl etkilemektedir? Bu çalışmada, online alışverişte hazır giyim ürünleri için ürün çeşitliliği, müşteri memnuniyeti ve müşterilerin sadakat niyetleri arasındaki ilişkiyi incelemek amaçlanmıştır. Veriler çevrimiçi anket formu aracılığıyla toplanmış ve 471 geçerli anket yanıtı analiz edilmiştir. Veri analizinde kullanılan istatistiksel yöntemler arasında frekans dağılımı, aritmetik ortalama, ölçüm modeli ve yapısal model testi yer almaktadır. Araştırma sonuçları, çevrimiçi hazır giyim alışverişlerinde ürün çeşitliliğinin müşteri memnuniyeti ve sadakat niyeti üzerinde pozitif ve anlamlı bir etki oluşturduğunu göstermektedir. Bu sonuçlara göre, hazır giyim ürünleri için geniş bir yelpaze sunan çevrimiçi alışveriş platformlarının, müşteri memnuniyetini olumlu bir şekilde etkilediği görülmektedir. Araştırmaya katılanlar, bu tür platformların geniş bir ürün yelpazesi sunma imkânı sağladığına inanmaktadır. Bu bulgular, çevrimiçi alışveriş platformlarının ürün çeşitliliğini artırdıklarında müşteri memnuniyetini artırma potansiyeline sahip olduğunu göstermektedir. Bu bağlamda, çevrimiçi alışveriş platformlarının ürün çeşitliliği stratejilerine odaklanmalarının önemi vurgulanmaktadır.
DOĞA BİLİMLERİNDEN SOSYAL BİLİMLERE: ÖRGÜTSEL ENTROPİ
Authors: DEMİREL Hatice Gökçe
Published: October 2023

Termodinamik yasaları doğa bilimlerinin en temel ve sarsılmaz yasalarıdır. Sosyal sistemler de doğa sistemleri gibi termodinamiğin ikinci yasası olan entropiye maruz kalmaktadır. Entropi, doğa bilimlerinde kendiliğinden gerçekleşen şeylerin evrendeki düzensizliği artırdığını ifade etmektedir. Sosyal bilimlerde ise genellikle bir amaç etrafında, bilinçli oluşturulmuş yapılar ve bu yapılar arasında enerji ve bilgi akışını kolaylaştıran süreçlerle entropiye karşı koyabilen mekanizmalar oluşturabilirler.

Örgütler insanlara amaçla bir yön vererek, enerjilerini ve zamanlarını üretime dönüştürerek, ön görülebilir davranış örüntüleriyle belirsizliği azaltarak bir düzen oluştururlar. Ancak örgütler de tüm sistemler gibi entropiden kaçamazlar.

Araştırmanın amacı örgütlerde düzeni oluşturan unsurlar (amaç, yapı, iletişim-etkileşim-bilgi) üzerinden entropiyi artıran ve azaltan durumları örgütsel düzeyde tespit etmektir. Kavramsal düzeyde yapılmış bu araştırmada, örgütlerin entropisini artıran ve azaltan unsurlara ilişkin tümevarımsal hipotezler ileri sürülmüştür. Örgüt amaçlarının parçası olduğu üst sistemin amaçları ve alt sistemi olan çalışanların kişisel amaçlarının örtüşmemesi, resmileştirme, merkezileşme derecesi, hiyerarşik rol basamakların artması entropiyi artırmaktadır. Uzmanlaşma, standardizasyon, sistem içinde birbiriyle ilişkili yapıların etkileşiminden ve çevreyle etkileşiminden sağlıklı bilgi üretebilen ve bu bilgiyi yayabilen örgütlerin entropisi azalmaktadır. Örgütlerin entropisine ilişkin bu hipotezlerin makro analiz düzeyinde öngörülebilir sonuçlar üretme kapasitesi yüksektir. Ancak analiz düzeyi küçüldükçe örgütlerin karmaşıklık düzeyi arttığından deterministik kaos kuramları çerçevesinde sonuçlar farklılık gösterebilir.
Locomotive maintenance scheduling: optimization approaches and a case study
Authors: Munari Pedro , Araujo Silvio A. de , Beker Eduardo , Camargo Victor C. B. , Campos Rafael , Hono Diego Y. , Pinelli Pedro , Rangel Socorro , Santos Maria L. T. , Santos Maristela O. , Senna Fernando R. , Teixeira Eduardo S. , Toledo Franklina M. B. , Tomazella Caio P. , Vieira Thiago , Cuminato José A.
Published: October 2023

The Locomotive Maintenance Scheduling Problem arises in the planning and control operations in railroad companies. In this problem, locomotives are parked in yards adjacent to maintenance shops where various maintenance tasks are performed. These shops have limited and specific service stations for each type of maintenance. The goal is to schedule locomotives to service stations aiming at satisfying the locomotive availability targets as well as reducing the backlog for unavailable locomotives by the end of the planning horizon. Despite its practical relevance, this problem has received limited attention in the literature, particularly regarding the development of decision-making tools. To reduce this research gap, we propose mathematical models and a heuristic approach based on the real-world case of MRS Logistics, a Brazilian railroad company. Computational experiments using data provided by the company indicate the effectiveness of the proposed models and heuristic, showing potential improvements for the company's operations
PM10 and Pseudomonas aeruginosa: effects on corneal epithelium
Authors: Somayajulu Mallika , McClellan Sharon A. , Muhammed Farooq , Wright Robert , Hazlett Linda D.
Published: October 2023

Purpose

In vivo data indicate that mouse corneas exposed to PM10 showed early perforation and thinning after infection with Pseudomonas aeruginosa. To understand the mechanisms underlying this finding, we tested the effects of PM10 and the mitochondria targeted anti-oxidant SKQ1 in immortalized human corneal epithelial cells (HCET) that were challenged with Pseudomonas aeruginosa strain 19660.

Methods

Mouse corneas were infected with strain 19660 after a 2 week whole-body exposure to PM10 or control air and assessed by clinical scores, slit lamp photography and western blot. HCET were exposed to 100μg/ml PM10 for 24h before challenge with strain 19660 (MOI 20). A subset of cells were pre-treated with 50nM SKQ1 for 1h before PM10 exposure. Phase contrast microscopy was used to study cell morphology, cell viability was measured by an MTT assay, and ROS by DCFH-DA. Levels of pro-inflammatory markers and anti-oxidant enzymes were evaluated by RT-PCR, western blot and ELISA. Reduced glutathione (GSH) and malondialdehyde (MDA) levels were evaluated by assay kits.

Results

In vivo, whole body exposure to PM10 vs. control air exposed mouse corneas showed early perforation and/or corneal thinning at 3 days post infection, accompanied by increased TNF-α and decreased SOD2 protein levels. In vitro, PM10 induced a dose dependent reduction in cell viability of HCET and significantly increased mRNA levels of pro-inflammatory molecules compared to control. Exposure to PM10 before bacterial challenge further amplified the reduction in cell viability and GSH levels. Furthermore, PM10 exposure also exacerbated the increase in MDA and ROS levels and phase contrast microscopy revealed more rounded cells after strain 19660 challenge. PM10 exposure also further increased the mRNA and protein levels of pro-inflammatory molecules, while anti-inflammatory IL-10 was decreased. SKQ1 reversed the rounded cell morphology observed by phase contrast microscopy, increased levels of MDA, ROS and pro-inflammatory molecules, and restored IL-10.

Conclusions

PM10 induces decreased cell viability, oxidative stress and inflammation in HCET and has an additive effect upon bacterial challenge. SKQ1 protects against oxidative stress and inflammation induced by PM10 after bacterial challenge by reversing these effects. The findings provide insight into mechanisms underlying early perforation and thinning observed in infected corneas of PM10 exposed mice.
Recasting the agreements to re-humanize STEM education
Authors: Imad Mays , Reder Michael , Rose Madelyn
Published: October 2023

The purpose of education is to understand and help address local and global problems to better society and the world. A key player in this endeavor should be STEM education, which has the potential to equip learners with the skills and knowledge necessary to address intersectional issues such as climate change, health and income disparities, racism, and political divisions. However, in this article we argue that despite the transformative potential of STEM education, it remains far removed from most people’s lived experiences and is detached from the real-world social, political, and economic contexts in which it exists. This detachment not only perpetuates existing inequities by failing to meet the specific needs and reflect the experiences of these communities, but it also hampers STEM education’s capacity to address the very local and global problems it is purported to solve. By remaining removed from the tangible, real-world contexts in which it exists, STEM education cannot fully harness its potential to better humanity. To address these issues, we propose humanizing STEM education by intentionally and explicitly grounding all work in the recognition of the inherent worth and dignity of all students, regardless of their background. We begin the article by critically examining the typically unspoken pre-existing assumptions or “agreements” that govern and dictate the norms of teaching and learning within STEM, ways of approaching framing STEM education that we often take for granted as necessary and true. We propose new agreements that expand the ways in which we think about STEM education, in hopes of making STEM education more accessible, inclusive, relevant, responsive, and reparative. Throughout, we deliberate on the notion of being human. We argue that to envision a future of humanistic STEM, one that is intentionally grounded in an ethics of care and equity for all, including the environment, it is necessary to continue to make visible and reimagine the unarticulated assumptions that underlie our current approaches to STEM education and practice.
Genomic and transcriptomic analyses of thyroid cancers identify DICER1 somatic mutations in adult follicular-patterned RAS-like tumors
Authors: Minna Emanuela , Devecchi Andrea , Pistore Federico , Paolini Biagio , Mauro Giuseppe , Penso Donata Alda , Pagliardini Sonia , Busico Adele , Pruneri Giancarlo , De Cecco Loris , Borrello Maria Grazia , Sensi Marialuisa , Greco Angela
Published: October 2023

Background

Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer (TC). Several genomic and transcriptomic studies explored the molecular landscape of follicular cell-derived TCs, and BRAFV600E, RAS mutations, and gene fusions are well-established drivers. DICER1 mutations were described in specific sets of TC patients but represent a rare event in adult TC patients.

Methods

Here, we report the molecular characterization of 30 retrospective follicular cell-derived thyroid tumors, comprising PTCs (90%) and poorly differentiated TCs (10%), collected at our Institute. We performed DNA whole-exome sequencing using patient-matched control for somatic mutation calling, and targeted RNA-seq for gene fusion detection. Transcriptional profiles established in the same cohort by microarray were investigated using three signaling-related gene signatures derived from The Cancer Genome Atlas (TCGA).

Results

The occurrence of BRAFV600E (44%), RAS mutations (13%), and gene fusions (13%) was confirmed in our cohort. In addition, in two patients lacking known drivers, mutations of the DICER1 gene (p.D1709N and p.D1810V) were identified. DICER1 mutations occur in two adult patients with follicular-pattern lesions, and in one of them a second concurrent DICER1 mutation (p.R459*) is also observed. Additional putative drivers include ROS1 gene (p.P2130A mutation), identified in a patient with a rare solid-trabecular subtype of PTC. Transcriptomics indicates that DICER1 tumors are RAS-like, whereas the ROS1-mutated tumor displays a borderline RAS-/BRAF-like subtype. We also provide an overview of DICER1 and ROS1 mutations in thyroid lesions by investigating the COSMIC database.

Conclusion

Even though small, our series recapitulates the genetic background of PTC. Furthermore, we identified DICER1 mutations, one of which is previously unreported in thyroid lesions. For these less common alterations and for patients with unknown drivers, we provide signaling information applying TCGA-derived classification.
Degranulation of human mast cells: modulation by P2 receptors’ agonists
Authors: Schulman Edward S. , Nishi Haruhisa , Pelleg Amir
Published: October 2023

Since the late 1970s, there has been an alarming increase in the incidence of asthma and its morbidity and mortality. Acute obstruction and inflammation of allergic asthmatic airways are frequently caused by inhalation of exogenous substances such as allergens cross-linking IgE receptors expressed on the surface of the human lung mast cells (HLMC). The degree of constriction of human airways produced by identical amounts of inhaled allergens may vary from day to day and even hour to hour. Endogenous factors in the human mast cell (HMC)’s microenvironment during allergen exposure may markedly modulate the degranulation response. An increase in allergic responsiveness may significantly enhance bronchoconstriction and breathlessness. This review focuses on the role that the ubiquitous endogenous purine nucleotide, extracellular adenosine 5’-triphosphate (ATP), which is a component of the damage-associated molecular patterns, plays in mast cells’ physiology. ATP activates P2 purinergic cell-surface receptors (P2R) to trigger signaling cascades resulting in heightened inflammatory responses. ATP is the most potent enhancer of IgE-mediated HLMC degranulation described to date. Current knowledge of ATP as it relates to targeted receptor(s) on HMC along with most recent studies exploring HMC post-receptor activation pathways are discussed. In addition, the reviewed studies may explain why brief, minimal exposures to allergens (e.g., dust, cat, mouse, and grass) can unpredictably lead to intense clinical reactions. Furthermore, potential therapeutic approaches targeting ATP-related enhancement of allergic reactions are presented.
Construction of an m6A- and neutrophil extracellular traps-related lncRNA model to predict hepatocellular carcinoma prognosis and immune landscape
Authors: Zhan Tian , Wang Wei , Guan Xiao , Bao Wei , Lu Na , Zhang Jianping
Published: October 2023

Purpose

To investigate the impact of N6-methyladenosine- (m6A) and neutrophil extracellular traps- (NETs) related lncRNAs (MNlncRNAs) on the prognosis of hepatocellular carcinoma (HCC).

Methods

We collected m6A and NETs-related genes from published studies. We identified the MNlncRNAs by correlation analysis. Cox regression and the least absolute selection operator (LASSO) method were used to select predictive MNlncRNAs. The expressions of predictive MNlncRNAs were detected by cell and tissue experiments. Survival, medication sensitivity, and immunological microenvironment evaluations were used to assess the model’s prognostic utility. Finally, we performed cellular experiments to further validate the model’s prognostic reliability.

Results

We obtained a total of 209 MNlncRNAs. 7 MNlncRNAs comprised the prognostic model, which successfully stratifies HCC patients, with the area under the curve (AUC) ranging from 0.7 to 0.8. In vitro tests confirmed that higher risk patients had worse prognosis. Risk score, immunological microenvironment, and immune checkpoint gene expression were all significantly correlated with each other in HCC. In the group at high risk, immunotherapy could be more successful. Cellular assays confirmed that HCC cells with high risk scores have a higher proliferation and invasive capacity.

Conclusion

The MNlncRNAs-related prognostic model aided in determining HCC prognosis, revealing novel therapeutic options, notably immunotherapy.
Exploring the dual role of B cells in solid tumors: implications for head and neck squamous cell carcinoma
Authors: Bao Jiantong , Betzler Annika C. , Hess Jochen , Brunner Cornelia
Published: October 2023

In the tumor milieu of head and neck squamous cell carcinoma (HNSCC), distinct B cell subpopulations are present, which exert either pro- or anti-tumor activities. Multiple factors, including hypoxia, cytokines, interactions with tumor cells, and other immune infiltrating lymphocytes (TILs), alter the equilibrium between the dual roles of B cells leading to cancerogenesis. Certain B cell subsets in the tumor microenvironment (TME) exhibit immunosuppressive function. These cells are known as regulatory B (Breg) cells. Breg cells suppress immune responses by secreting a series of immunosuppressive cytokines, including IL-10, IL-35, TGF-β, granzyme B, and adenosine or dampen effector TILs by intercellular contacts. Multiple Breg phenotypes have been discovered in human and mouse cancer models. However, when compartmentalized within a tertiary lymphoid structure (TLS), B cells predominantly play anti-tumor effects. A mature TLS contains a CD20+ B cell zone with several important types of B cells, including germinal-center like B cells, antibody-secreting plasma cells, and memory B cells. They kill tumor cells via antibody-dependent cytotoxicity and phagocytosis, and local complement activation effects. TLSs are also privileged sites for local T and B cell coordination and activation. Nonetheless, in some cases, TLSs may serve as a niche for hidden tumor cells and indicate a bad prognosis. Thus, TIL-B cells exhibit bidirectional immune-modulatory activity and are responsive to a variety of immunotherapies. In this review, we discuss the functional distinctions between immunosuppressive Breg cells and immunogenic effector B cells that mature within TLSs with the focus on tumors of HNSCC patients. Additionally, we review contemporary immunotherapies that aim to target TIL-B cells. For the development of innovative therapeutic approaches to complement T-cell-based immunotherapy, a full understanding of either effector B cells or Breg cells is necessary.
Innate lymphoid cells and tumor-derived lactic acid: novel contenders in an enduring game
Authors: Marciniak Mateusz , Wagner Marek
Published: October 2023

Aerobic glycolysis, also known as the Warburg effect, has for a prolonged period of time been perceived as a defining feature of tumor metabolism. The redirection of glucose utilization towards increased production of lactate by cancer cells enables their rapid proliferation, unceasing growth, and longevity. At the same time, it serves as a significant contributor to acidification of the tumor microenvironment, which, in turn, imposes substantial constraints on infiltrating immune cells. Here, we delve into the influence of tumor-derived lactic acid on innate lymphoid cells (ILCs) and discuss potential therapeutic approaches. Given the abundance of ILCs in barrier tissues such as the skin, we provide insights aimed at translating this knowledge into therapies that may specifically target skin cancer.
Refined control of CRISPR-Cas9 gene editing in Clostridium sporogenes: the creation of recombinant strains for therapeutic applications
Authors: Kubiak Aleksandra M. , Claessen Luuk , Zhang Yanchao , Khazaie Khashayarsha , Bailey Tom S.
Published: October 2023

Despite considerable clinical success, the potential of cancer immunotherapy is restricted by a lack of tumour-targeting strategies. Treatment requires systemic delivery of cytokines or antibodies at high levels to achieve clinically effective doses at malignant sites. This is exacerbated by poor penetration of tumour tissue by therapeutic antibodies. High-grade immune-related adverse events (irAEs) occur in a significant number of patients (5-15%, cancer- and therapeutic-dependent) that can lead to lifelong issues and can exclude from treatment patients with pre-existing autoimmune diseases. Tumour-homing bacteria, genetically engineered to produce therapeutics, is one of the approaches that seeks to mitigate these drawbacks. The ability of Clostridium sporogenes to form spores that are unable to germinate in the presence of oxygen (typical of healthy tissue) offers a unique advantage over other vectors. However, the limited utility of existing gene editing tools hinders the development of therapeutic strains. To overcome the limitations of previous systems, expression of the Cas9 protein and the gRNA was controlled using tetracycline inducible promoters. Furthermore, the components of the system were divided across two plasmids, improving the efficiency of cloning and conjugation. Genome integrated therapeutic genes were assayed biochemically and in cell-based functional assays. The potency of these strains was further improved through rationally-conceived gene knock-outs. The new system was validated by demonstrating the efficient addition and deletion of large sequences from the genome. This included the creation of recombinant strains expressing two pro-inflammatory cytokines, interleukin-2 (IL-2) and granulocyte macrophage-colony stimulating factor (GM-CSF), and a pro-drug converting enzyme (PCE). A comparative, temporal in vitro analysis of the integrant strains and their plasmid-based equivalents revealed a substantial reduction of cytokine activity in chromosome-based constructs. To compensate for this loss, a 7.6 kb operon of proteolytic genes was deleted from the genome. The resultant knock-out strains showed an 8- to 10-fold increase in cytokine activity compared to parental strains.
Multifaceted roles and regulation of nucleotide-binding oligomerization domain containing proteins
Authors: Dixon Charneal L. , Wu Amy , Fairn Gregory D.
Published: October 2023

Nucleotide-binding oligomerization domain-containing proteins, NOD1 and NOD2, are cytosolic receptors that recognize dipeptides and tripeptides derived from the bacterial cell wall component peptidoglycan (PGN). During the past two decades, studies have revealed several roles for NODs beyond detecting PGN fragments, including activation of an innate immune anti-viral response, NOD-mediated autophagy, and ER stress induced inflammation. Recent studies have also clarified the dynamic regulation of NODs at cellular membranes to generate specific and balanced immune responses. This review will describe how NOD1 and NOD2 detect microbes and cellular stress and detail the molecular mechanisms that regulate activation and signaling while highlighting new evidence and the impact on inflammatory disease pathogenesis.
Substantial heterogeneity of inflammatory cytokine production and its inhibition by a triple cocktail of toll-like receptor blockers in early sepsis
Authors: Buys Willem , Bick Alexandra , Madel Rabea J. , Westendorf Astrid M. , Buer Jan , Herbstreit Frank , Kirschning Carsten J. , Peters Jürgen
Published: October 2023

Introduction

Early sepsis is a life-threatening immune dysregulation believed to feature a “cytokine storm” due to activation of pattern recognition receptors by pathogen and danger associated molecular patterns. However, treatments with single toll-like receptor (TLR) blockers have shown no clinical benefit. We speculated that sepsis patients at the time of diagnosis are heterogeneous in relation to their cytokine production and its potential inhibition by a triple cocktail of TLR blockers. Accordingly, we analyzed inflammatory cytokine production in whole blood assays from early sepsis patients and determined the effects of triple TLR-blockade.

Methods

Whole blood of 51 intensive care patients sampled within 24h of meeting Sepsis-3 criteria was incubated for 6h without or with specific TLR2, 4, and 7/8 stimuli or suspensions of heat-killed S. aureus or E. coli bacteria as pan-TLR challenges, and also with a combination of monoclonal antibodies against TLR2 and 4 and chloroquine (endosomal TLR inhibition), subsequent to dose optimization. Concentrations of tumor necrosis factor (TNF), Interleukin(IL)-6, IL-8, IL-10, IL-1α and IL-1β were measured (multiplex ELISA) before and after incubation. Samples from 11 sex and age-matched healthy volunteers served as controls and for dose-finding studies.

Results

Only a fraction of sepsis patient samples revealed ongoing cytokine production ex vivo despite sampling within 24 h of first meeting Sepsis-3 criteria. In dose finding studies, inhibition of TLR2, 4 and endosomal TLRs reliably suppressed cytokine production to specific TLR agonists and added bacteria. However, inflammatory cytokine production ex vivo was only suppressed in the high cytokine producing samples but not in the majority. The suppressive response to TLR-blockade correlated both with intraassay inflammatory cytokine production (r=0.29–0.68; p<0.0001–0.04) and cytokine baseline concentrations (r=0.55; p<0.0001).

Discussion

Upon meeting Sepsis-3 criteria for less than 24 h, a mere quarter of patient samples exhibits a strong inflammatory phenotype, as characterized by increased baseline inflammatory cytokine concentrations and a stark TLR-dependent increase upon further ex vivo incubation. Thus, early sepsis patient cohorts as defined by Sepsis-3 criteria are very heterogeneous in regard to inflammation. Accordingly, proper ex vivo assays may be useful in septic individuals before embarking on immunomodulatory treatments.
Re-evaluating serum angiotensin-converting enzyme in sarcoidosis
Authors: Zheng Shi-yue , Du Xin , Dong Jian-zeng
Published: October 2023

Sarcoidosis is a systemic inflammatory disease of unknown etiology, which mainly affects the lungs and lymph nodes, as well as extrapulmonary organs. Its incidence, and prevalence rate, and disease course largely vary with regions and populations globally. The clinical manifestations of sarcoidosis depend on the affected organs and the degree of severity, and the diagnosis is mainly based on serum biomarkers, radiographic, magnetic resonance, or positron emission tomography imaging, and pathological biopsy. Noncaseating granulomas composing T cells, macrophages, epithelioid cells, and giant cells, were observed in a pathological biopsy, which was the characteristic pathological manifestation of sarcoidosis. Angiotensin-converting enzyme (ACE) was first found in the renin–angiotensin–aldosterone system. Its main function is to convert angiotensin I (Ang I) into Ang II, which plays an important role in regulating blood pressure. Also, an ACE insertion/deletion polymorphism exists in the human genome, which is involved in the occurrence and development of many diseases, including hypertension, heart failure, and sarcoidosis. The serum ACE level, most commonly used as a biomarker in diagnosing sarcoidosis, in patients with sarcoidosis increases. because of epithelioid cells and giant cells of sarcoid granuloma expressing ACE. Thus, it serves as the most commonly used biomarker in the diagnosis of sarcoidosis and also aids in analyzing its therapeutic effect and prognosis in patients with sarcoidosis.
Plankton community structure in response to hydrothermal iron inputs along the Tonga-Kermadec arc
Authors: Mériguet Zoé , Vilain Marion , Baudena Alberto , Tilliette Chloé , Habasque Jérémie , Lebourges-Dhaussy Anne , Bhairy Nagib , Guieu Cécile , Bonnet Sophie , Lombard Fabien
Published: October 2023

The Western Tropical South Pacific (WTSP) basin has been identified as a hotspot of atmospheric dinitrogen fixation due to the high dissolved iron ([DFe]) concentrations (up to 66 nM) in the photic layer linked with the release of shallow hydrothermal fluids along the Tonga-Kermadec arc. Yet, the effect of such hydrothermal fluids in structuring the plankton community remains poorly studied. During the TONGA cruise (November-December 2019), we collected micro- (20-200 μm) and meso-plankton (>200 μm) samples in the photic layer (0-200 m) along a west to east zonal transect crossing the Tonga volcanic arc, in particular two volcanoes associated with shallow hydrothermal vents (< 500 m) in the Lau Basin, and both sides of the arc represented by Melanesian waters and the South Pacific Gyre. Samples were analyzed by quantitative imaging (FlowCam and ZooScan) and then coupled with acoustic observations, allowing us to study the potential transfer of phytoplankton blooms to higher planktonic trophic levels. We show that micro- and meso-plankton exhibit high abundances and biomasses in the Lau Basin and, to some extent, in Melanesian waters, suggesting that shallow hydrothermal inputs sustain the planktonic food web, creating productive waters in this otherwise oligotrophic region. In terms of planktonic community structure, we identified major changes with high [DFe] inputs, promoting the development of a low diversity planktonic community dominated by diazotrophic cyanobacteria. Furthermore, in order to quantify the effect of the shallow hydrothermal vents on chlorophyll a concentrations, we used Lagrangian dispersal models. We show that chlorophyll a concentrations were significantly higher inside the Lagrangian plume, which came into contact with the two hydrothermal sites, confirming the profound impact of shallow hydrothermal vents on plankton production.
An analytic model of typhoon wind field and simulation of storm tides
Authors: Sun Zhilin , Ding Kaixuan , Li Zongyu , Chen Fanjun , Zhong Shanhong
Published: October 2023

Storm tides have intensified due to global climate warming, with limited attention given to storm current velocity (SCV) due to data scarcity during hurricanes/typhoons and limitations in existing wind models’ accuracy. We propose an analytic model incorporating sea-surface resistance into the gradient wind equation, offering a theoretically robust approach. Through rigorous verification against measured data, our model demonstrates significant accuracy improvement compared to established models. Simulating storm tides during Typhoon Rammasun using our approach reveals strong agreement between calculated SCVs and measured data, surpassing the performance of the Holland model. Notably, typhoon storm surges primarily respond to pressure, while SCVs are predominantly governed by wind speed in open sea. The highest water level aligns with the lowest pressure, with maximum SCVs trailing the maximum wind radius. SCVs significantly exceed astronomical tidal current velocities (ACVs) in the open sea, reaching a maximum of 3.57 m/s. Areas where the SCV-to-ACV ratio exceeds 3 constitute 21.4% of the study area. Combining our wind model with Typhoon SCV simulations provides valuable insights into storm tide dynamics, advancing our understanding of storm tide mechanisms and informing mitigation strategies.
Habitat modeling of mature albacore (Thunnus alalunga) tuna in the Indian Ocean
Authors: Mondal Sandipan , Lee Ming-An
Published: October 2023

This study examined the spatial distribution of mature albacore tuna (Thunnus alalunga) in the Indian Ocean between 1998 and 2016 (October to March) using environmental factors and logbook fishery data from Taiwanese longliners. We collected the albacore tuna fishery data, including fishing location, fishing effort, number of catch, fishing duration, and fish weight. The optimal limits for oxygen, temperature, salinity, and sea surface height for mature albacore tuna, as determined by generalized additive modeling, were 5–5.3 mL/L, 25–29°C, 34.85–35.55 PSU, and 0.5–0.7 m, respectively. The optimal models were determined to be a geometric mean–derived habitat suitability–based model constructed with oxygen, temperature, and salinity and a generalized additive model constructed with oxygen, temperature, salinity, and sea surface height. From October to March, mature albacore tuna remained between 10°S and 30°S. Our study concurs with previous studies on albacore tuna in the region that suggest that the spawning area is located between 10-25˚S, and that spawning occurs primarily between November and January. This study reveals the spatial patterns and environmental preferences of mature albacore tuna in the Indian Ocean which may help put in place better management practices for this fishery.
Identification of rare microbial colonizers of plastic materials incubated in a coral reef environment
Authors: Singleton Sebastian L. , Davis Edward W. , Arnold Holly K. , Daniels An Mei Y. , Brander Susanne M. , Parsons Rachel J. , Sharpton Thomas J. , Giovannoni Stephen J.
Published: October 2023

Plastic waste accumulation in marine environments has complex, unintended impacts on ecology that cross levels of community organization. To measure succession in polyolefin-colonizing marine bacterial communities, an in situ time-series experiment was conducted in the oligotrophic coastal waters of the Bermuda Platform. Our goals were to identify polyolefin colonizing taxa and isolate bacterial cultures for future studies of the biochemistry of microbe-plastic interactions. HDPE, LDPE, PP, and glass coupons were incubated in surface seawater for 11 weeks and sampled at two-week intervals. 16S rDNA sequencing and ATR-FTIR/HIM were used to assess biofilm community structure and chemical changes in polymer surfaces. The dominant colonizing taxa were previously reported cosmopolitan colonizers of surfaces in marine environments, which were highly similar among the different plastic types. However, significant differences in rare community composition were observed between plastic types, potentially indicating specific interactions based on surface chemistry. Unexpectedly, a major transition in community composition occurred in all material treatments between days 42 and 56 (p < 0.01). Before the transition, Alteromonadaceae, Marinomonadaceae, Saccharospirillaceae, Vibrionaceae, Thalassospiraceae, and Flavobacteriaceae were the dominant colonizers. Following the transition, the relative abundance of these taxa declined, while Hyphomonadaceae, Rhodobacteraceae and Saprospiraceae increased. Over the course of the incubation, 8,641 colonizing taxa were observed, of which 25 were significantly enriched on specific polyolefins. Seven enriched taxa from families known to include hydrocarbon degraders (Hyphomonadaceae, Parvularculaceae and Rhodobacteraceae) and one n-alkane degrader (Ketobacter sp.). The ASVs that exhibited associations with specific polyolefins are targets of ongoing investigations aimed at retrieving plastic-degrading microbes in culture.
Role of complement in myasthenia gravis
Authors: San Pyae Phyo , Jacob Saiju
Published: October 2023

Myasthenia gravis is a prototypic neuroimmune disorder with autoantibodies targeting the acetylcholine receptor complex at the neuromuscular junction. Patients present with mainly ocular muscle weakness and tend to have a generalized muscle weakness later in the clinical course. The weakness can be severe and fatal when bulbar muscles are heavily involved. Acetylcholine receptor antibodies are present in the majority of patients and are of IgG1 and IgG3 subtypes which can activate the complement system. The complement involvement plays a major role in the neuromuscular junction damage and the supporting evidence in the literature is described in this article. Complement therapies were initially studied and approved for paroxysmal nocturnal hemoglobinuria and in the past decade, those have also been studied in myasthenia gravis. The currently available randomized control trial and real-world data on the efficacy and safety of the approved and investigational complement therapies are summarized in this review.
An image caption model based on attention mechanism and deep reinforcement learning
Authors: Bai Tong , Zhou Sen , Pang Yu , Luo Jiasai , Wang Huiqian , Du Ya
Published: October 2023

Image caption technology aims to convert visual features of images, extracted by computers, into meaningful semantic information. Therefore, the computers can generate text descriptions that resemble human perception, enabling tasks such as image classification, retrieval, and analysis. In recent years, the performance of image caption has been significantly enhanced with the introduction of encoder-decoder architecture in machine translation and the utilization of deep neural networks. However, several challenges still persist in this domain. Therefore, this paper proposes a novel method to address the issue of visual information loss and non-dynamic adjustment of input images during decoding. We introduce a guided decoding network that establishes a connection between the encoding and decoding parts. Through this connection, encoding information can provide guidance to the decoding process, facilitating automatic adjustment of the decoding information. In addition, Dense Convolutional Network (DenseNet) and Multiple Instance Learning (MIL) are adopted in the image encoder, and Nested Long Short-Term Memory (NLSTM) is utilized as the decoder to enhance the extraction and parsing capability of image information during the encoding and decoding process. In order to further improve the performance of our image caption model, this study incorporates an attention mechanism to focus details and constructs a double-layer decoding structure, which facilitates the enhancement of the model in terms of providing more detailed descriptions and enriched semantic information. Furthermore, the Deep Reinforcement Learning (DRL) method is employed to train the model by directly optimizing the identical set of evaluation indexes, which solves the problem of inconsistent training and evaluation standards. Finally, the model is trained and tested on MS COCO and Flickr 30 k datasets, and the results show that the model has improved compared with commonly used models in the evaluation indicators such as BLEU, METEOR and CIDEr.
How far neuroscience is from understanding brains
Authors: Roland Per E.
Published: October 2023

The cellular biology of brains is relatively well-understood, but neuroscientists have not yet generated a theory explaining how brains work. Explanations of how neurons collectively operate to produce what brains can do are tentative and incomplete. Without prior assumptions about the brain mechanisms, I attempt here to identify major obstacles to progress in neuroscientific understanding of brains and central nervous systems. Most of the obstacles to our understanding are conceptual. Neuroscience lacks concepts and models rooted in experimental results explaining how neurons interact at all scales. The cerebral cortex is thought to control awake activities, which contrasts with recent experimental results. There is ambiguity distinguishing task-related brain activities from spontaneous activities and organized intrinsic activities. Brains are regarded as driven by external and internal stimuli in contrast to their considerable autonomy. Experimental results are explained by sensory inputs, behavior, and psychological concepts. Time and space are regarded as mutually independent variables for spiking, post-synaptic events, and other measured variables, in contrast to experimental results. Dynamical systems theory and models describing evolution of variables with time as the independent variable are insufficient to account for central nervous system activities. Spatial dynamics may be a practical solution. The general hypothesis that measurements of changes in fundamental brain variables, action potentials, transmitter releases, post-synaptic transmembrane currents, etc., propagating in central nervous systems reveal how they work, carries no additional assumptions. Combinations of current techniques could reveal many aspects of spatial dynamics of spiking, post-synaptic processing, and plasticity in insects and rodents to start with. But problems defining baseline and reference conditions hinder interpretations of the results. Furthermore, the facts that pooling and averaging of data destroy their underlying dynamics imply that single-trial designs and statistics are necessary.
Family characteristics, phylogenetic reconstruction, and potential applications of the plant BAHD acyltransferase family
Authors: Xu Donghuan , Wang Zhong , Zhuang Weibing , Wang Tao , Xie Yinfeng
Published: October 2023

The BAHD acyltransferase family is a class of proteins in plants that can acylate a variety of primary and specialized secondary metabolites. The typically acylated products have greatly improved stability, lipid solubility, and bioavailability and thus show significant differences in their physicochemical properties and pharmacological activities. Here, we review the protein structure, catalytic mechanism, and phylogenetic reconstruction of plant BAHD acyltransferases to describe their family characteristics, acylation reactions, and the processes of potential functional differentiation. Moreover, the potential applications of the BAHD family in human activities are discussed from the perspectives of improving the quality of economic plants, enhancing the efficacy of medicinal plants, improving plant biomass for use in biofuel, and promoting stress resistance of land plants. This review provides a reference for the research and production of plant BAHD acyltransferases.
A peptide encoded by a highly conserved gene belonging to the genus Streptomyces shows antimicrobial activity against plant pathogens
Authors: Jeon Byeong Jun , Yoo Nayeon , Kim Jeong Do , Choi Jaeyoung
Published: October 2023

The genus Streptomyces has been unceasingly highlighted for the versatility and diversity of the antimicrobial agents they produce. Moreover, it is a heavily sequenced taxon in the phylum Actinobacteria. In this study, 47 sequence profiles were identified as proteins highly conserved within the genus Streptomyces. Significant hits to the 38 profiles were found in more than 2000 Streptomyces genomes, 11 of which were further conserved in more than 90% of Actinobacterial genomes analyzed. Only a few genes corresponding to these sequence profiles were functionally characterized, which play regulatory roles in the morphology and biosynthesis of antibiotics. Here a highly conserved sequence, namely, SHC-AMP (Streptomyces highly conserved antimicrobial peptide), which exhibited antimicrobial activity against bacterial and fungal plant pathogens, was reported. In particular, Arabidopsis thaliana was effectively protected against infection with Pseudomonas syringae pv. tomato DC3000 by treatment with this peptide. Results indicated the potential application of this peptide as an antimicrobial agent for control of plant diseases. Our results suggest putative target genes for controlling Streptomyces spp., including the one exhibiting antimicrobial activity against a wide range of phytopathogens.