bluuebunny/crossref_metadata_2025 huggingface dataset:
ОСОБЛИВОСТІ КОНЦЕПЦІЙ ЦІННІСНО-ОРІЄНТОВАНОГО ЛІДЕРСТВА
Authors: Максимчук Надія
Published: November 2024

У статті розглядаються нові підходи до дослідження важливості ціннісно-орієнтованого лідерства та його ролі в управлінській парадигмі сучасності. Аналізуються складові лідерства, описуються особливості взаємозв’язку рівня розвитку цілісності особистості із результативними параметрами управлінської діяльності. Систематизовано основні підходи до сутності та структури концепцій ціннісно-орієнтованого лідерства. Доведено важливу роль і значення розвитку потенціалу лідерського впливу. Окреслено проблеми формування лідерської компетентності успішних керівників. Відмічено феноменологічний рівень впливу лідерських якостей керівника на мотиваційну діяльність підлеглих. Виокремлено основні критерії розвитку обдарованої особистості, що наділена лідерськими властивостями. Розглянуто основні положення сучасних концепцій лідерства, в основі яких розкриваються основні ціннісні принципи розвитку особистості в процесі життєдіяльності. Обгрунтовано, що лідерство починається з характеру особистості, відображаючи внутрішню її сутність. Різні етапи становлення характеру базуються на фундаментальній ідеї про те, що існують певні принципи, які керують успішністю людини, природні закони, що діють у людському вимірі успішного функціонування і впливають на нього. Адже характер безпосередньо впливає на ваші дії, а дії впливають на характер. Характер є певним «фундаментом», що дає сили пережити різні випробування життя. З цього випливає, що саме характер є основою для лідерства, що орієнтоване на людину. Розкрито роль чеснот для формування характеру, оскільки вони є основою його. Чесноти такі як прийняття себе, практичне критичне судження, що ґрунтується на щоденній рефлексії, хоробрість, яка породжує відчуття правди і справедливості та активує моральну чутливість, зваженість або самоконтроль та справедливість, якщо наше лідерство зорієнтоване на людину. Ще в давнину Аристотель стверджував: «Пізнання себе – це початок усієї мудрості». Тільки через саморефрексію, ми зможемо, розкривши власний потенціал, стати успішним ціннісно-орієнтованим лідером.
Enfoque de la Eritrocitosis: a propósito de un caso de Estenosis y Trombosis Concomitante de las arterias renales en una paciente con Policitemia Vera
Authors: Vélez Aguirre Juan , Contreras Saldarriaga Jorge , Bermúdez Montero Jorge
Published: November 2024

Introducción: la policitemia Vera es la neoplasia mieloproliferativa más común y entre sus complicaciones más frecuentes, destacan los eventos trombo-embólicos (predominantemente de componente arterial), relacionados con aumento de la morbimortalidad. A la fecha, además, se han presentado algunos reportes de casos de estenosis de las arterias renales en pacientes con policitemia Vera concomitante, que sugieren una relación fisiopatológica entre ambas entidades, pero la evidencia actual sigue siendo contradictoria. Caso clínico: a continuación, se expone el caso de una mujer de 73 años que se presentó con eritrocitosis y un cuadro concomitante de trombosis y estenosis de las arterias renales, en la que se descartó causas secundarias relacionadas y se llegó al diagnóstico de policitemia Vera luego de la confirmación de niveles bajos de eritropoyetina y detección de la mutación JAK-2 clásica. Con base en este caso clínico y la pertinente revisión de la literatura, se propone un algoritmo diagnóstico como parte del enfoque de la eritrocitosis. Conclusión: nuestro reporte de caso sugiere que además de los fenómenos trombóticos clásicos, existe una posible relación entre la policitemia Vera y la estenosis de las arterias renales, como previos trabajos habían observado.
Business ecosystem management in the conditions new normality and transcendence
Authors: Sahaidak Mykhailo , Biletskyi Yaroslav
Published: November 2024

The article examines the essence of the concept, examines the elements and their inherent features of the business ecosystem, substantiates the approaches to effective management in the conditions of new normality and transcendence. The signs of a business ecosystem presented in the article are at first glance inherent in the characteristics of any enterprise, institution or organization, however, we note that ecosystems or turquoise organizations represent the next stage of consciousness development, where traditional concepts and methods are questioned and the organization is considered as a living organism, not a mechanical system. In the context of the transcendental development of business ecosystems, environmental turbulence and growing uncertainty lead to a decrease in the effectiveness of traditional management tools, at the same time, these characteristics can become a catalyst for new opportunities and non-standard management solutions that can significantly strengthen their position in the market and affect corporate synergistic effects, contribute to the formation of new connections and ideas, which will subsequently lead to the introduction of innovations and the development of business ecosystems.
Transcendence in the context of management is considered as a concept that covers aspects that go beyond the established boundaries of existing experience, understanding or perception, standard models, conditions and approaches in managing business ecosystems. Management of the business ecosystem in the conditions of new normality and transcendence requires the use of integrated approaches and strategies that can go beyond traditional tools, methods and models. Envisioning the transcendence of management means changing the way you think and understanding that standard models and methods may become ineffective or insufficient in the new normal.
Business ecosystems whose leaders are focused on transcendental development in the conditions of the new normality have the greatest chances for business viability, recovery and success. In this context, the article examines transcendental leadership, which refers to the concept of leadership that goes beyond traditional models and focuses on a deeper understanding and approach to managing people, organizations, and change.
Steiermärkisches Baurecht
Authors: Neger Thomas , Ulm Andres , Dreier Pascal , Doriath Marie
Published: November 2024

Rechtssicherheit für Bauvorhaben in der Steiermark Das Steiermärkische Baugesetz 1995 (Stmk BauG) bildet im Bundesland Steiermark die zentrale Rechtsgrundlage für Bauvorhaben. Es regelt die notwendigen Bewilligungsverfahren für Neubauten, Erweiterungen, Umbauten sowie Nutzungsänderungen baulicher Anlagen und umfasst baupolizeiliche Maßnahmen wie Beseitigungsaufträge, Nutzungsverbote, Baustopps und Versiegelungen. Abgesehen von bestimmten, gesetzlich festgelegten Ausnahmen, die eine Genehmigung nach anderen Rechtsvorschriften erfordern, zum Beispiel im Straßen- oder Abfallrecht, ist das Stmk BauG die maßgebliche Rechtsgrundlage für die meisten baulichen Maßnahmen. Zudem enthält es verwaltungsstrafrechtliche Bestimmungen, welche Sanktionen für das Abweichen von gesetzlichen Verpflichtungen vorsehen. Dieser Kommentar vereint wichtige Gesetzesmaterialien - Regierungsvorlagen, Ausschussberichte und Erläuterungen - sowie richtungsweisende Entscheidungen des Verwaltungs- und Verfassungsgerichtshofs. Ziel ist es, den Anwendenden des Gesetzes einen umfassenden und praxisorientierten Einblick zu geben. Die Autor*innen, allesamt erfahrene Rechtsanwält*innen im öffentlichen Bau-, Raumordnungs- und Gemeinderecht, bereichern die Kommentierung mit ihrem Fachwissen aus ihrer beruflichen Praxis.
Correlation of Carnitine Levels to Methionine and Lysine Intake
Authors: Krajčovičová-Kudláčková M , Šimončič R , Béderová A , Babinská K , Béder I
Published: November 2024

Plasma carnitine levels were measured in two alternative nutrition groups – strict vegetarians (vegans) and lactoovovegetarians (vegetarians consuming limited amounts of animal products such as milk products and eggs). The results were compared to an average sample of probands on mixed nutrition (omnivores). Carnitine levels were correlated with the intake of essential amino acids, methionine and lysine (as substrates of its endogenous synthesis), since the intake of carnitine in food is negligible in the alternative nutrition groups (the highest carnitine content is in meat, lower is in milk products, while fruit, cereals and vegetables contain low or no carnitine at all). An average carnitine level in vegans was significantly reduced with hypocarnitinemia present in 52.9 % of probands. Similarly, the intake of methionine and lysine was significantly lower in this group due to the exclusive consumption of plant proteins with reduced content of these amino acids. Carnitine level in lactoovovegetarians was also significantly reduced, but the incidence of values below 30 m mol/l was lower than in vegans representing 17.8 % vs. 3.3 % in omnivores. Intake of methionine and lysine was also significantly reduced in this group, but still higher compared to vegans (73 % of protein intake covered by plant proteins). Significant positive correlation of carnitine levels with methionine and lysine intake in alternative nutrition groups indicates that a significant portion of carnitine requirement is covered by endogenous synthesis. Approximately two thirds of carnitine requirement in omnivores comes from exogenous sources. The results demonstrate the risks of alternative nutrition with respect to the intake of essential amino acids, methionine and lysine, and with respect to the intake and biosynthesis of carnitine.
Neurophysiological and Behavioral Responses to Olfactory Stimuli in the Snail Helix pomatia L.
Authors: Voss M
Published: November 2024

Some aspects of olfactory sensitivity in the pulmonate Helix pomatia L. were studied by means of neurophysiological and behavioral methods. Single fiber recordings were carried out in the olfactory nerve of the posterior tentacles. Olfactory stimulations with different odors were performed by means of a continuous air stream. The order of neuronal sensitivity to different odors was as follows: ethanol ³ ethyl acetate > pentanol > hexanol > octanol > diethyl malonate > vanillin. Furthermore, the results revealed a relative specificity for some substances. A comparison between neurophysiological and behavioral data shows that those substances, which cause the highest increases in impulse frequency, also evoke a behavioral avoidance reaction.
BERN SÖZLEŞMESİ’NİN TARİHSEL GELİŞİMİ, SÖZLEŞME KORUMASININ İLKELERİ VE KORUNAN ESERLER İLE MENFAATLER
Authors: Gökçek Hasan Serat
Published: November 2024

Bern Sözleşmesi’nin fikir ve sanat eserlerinin yeknesak ve evrensel bir tarzda korunmasında temel bir araç halini alması yüz yılı aşan yavaş ancak istikrarlı bir devinimin sonucudur. Sözleşme’nin ve Sözleşme’den doğan Bern Birliği’nin 1886 yılında İsviçre’nin Bern şehrinde başlayan yolculuğunda, 1896 yılındaki ilk revizyondan 1971 yılında gerçekleştirilen son revizyona kadar Sözleşme defalarca gözden geçirilmiştir. Bütün bu süreçte Sözleşme’nin muhtelif metinlerine taraf ülke sayısı artmaya devam etmiş ve bu revizyonlar ile Sözleşme’nin fikir ve sanat eserleri üzerindeki menfaatlerin korunması bakımından ortaya koyduğu çerçeve belirgin hale gelmiştir.

Bu bağlamda Sözleşme’nin 1886 yılında milli muamele ilkesi ve tercüme hakkı ile başlayan yolculuğu, önce genişleyen asgari haklar sepeti ile desteklenmiştir. Daha sonraları doğrudan doğruya Sözleşme nezdinde eser olarak kabul edilen ürünlerin sayısı da artmıştır. Ayrıca Sözleşme korumasının, eserin kaynak ülkesindeki herhangi bir formalitenin yerine getirilmesine bağlı olmadığı ilkesiyle, Sözleşme korumasının başlangıcı adeta eserin yaratılma anı olarak sabitlenmiştir. Bugün gelinen noktada, Sözleşme’ye taraf ülke sayısının artmasıyla eser korumasının asgari standardı, Sözleşme’nin öngördüğü koruma olmuştur. Hem Bern Sözleşmesi’nin tarihinin hem de bu Sözleşme’nin öngördüğü korumanın çeşitli yönlerden ele alınması bu nedenle büyük bir öneme sahiptir.

Eldeki çalışmada öncelikle Sözleşme’nin ortaya çıkışını gerektiren nedenler ve Sözleşme’nin ortaya çıkışı ele alınmış ve bu kapsamda Türkiye’nin de Sözleşme’ye taraf oluşuna yer verilmiştir. Bunun ardından Sözleşme’nin eser üzerindeki menfaatlerin korunmasına yönelik getirdiği temel ilkeler işlenmiş ve korunan eserler ile korunan eserler üzerindeki menfaatlerin neler olduğu incelenmiştir.
AHLÂK ve HUKUKUN KÖKENLERİ HAKKINDA BİR İNCELEME
Authors: Topuzkanamış Engin
Published: November 2024

Hukuk felsefecilerinin, hukuk ve ahlâk arasındaki ilişki hakkında süregiden ve bitmek bilmeyen tartışmaları, bilimsel verileri pek dikkate almadan sürdürülmektedir. Hukuk sosyolojisi, ahlâk ve hukukun toplumsal kaynaklarına vurgu yapsa da son otuz kırk yıl içerisinde gerek nörobilim alanındaki çalışmalar gerekse hayvan davranışlarının daha yakından gözlenmesi ile elde edilen bilgiler henüz gerekli ilgiyi görmemiştir. Ahlâkî “tabiatımız” metafizik bir ilke veya evrensel bir aşkın yasadan değil, bir arada yaşama zorunluluğunun ortaya çıkardığı ilişkilerden doğar. Hem hukuk hem de ahlâk insan tekine dışsaldır. Her ikisi de güç ilişkilerinin bir sonucudur. İnsanın bireysel olarak etik varlığını inşa edebilmesi, bu kavramların gerçek mahiyetinin araştırılması ile mümkündür.
Hereditary alpha tryptasemia: elevated tryptase, female sex, thyroid disorders, and anaphylaxis
Authors: Puxkandl Viktoria , Aigner Stefan , Hoetzenecker Wolfram , Altrichter Sabine
Published: November 2024

Introduction

The clinical significance of elevated baseline serum tryptase (BST) in the absence of mast cell disorders or allergic reactions has long been unclear. Recently, a genetic variation of the TPSAB1 gene, which among others encodes for alpha tryptase, has been reported and named hereditary alpha tryptasemia (HaT). HaT has been linked to various manifestations, including severe allergic reactions. However, clinical studies are limited. In this study, we aimed to determine HaT prevalence and characterize its clinical manifestations in patients at a specialized allergy center.

Methods

From January 2022 to December 2023, patients with elevated BST at least once were screened for HaT at the outpatient clinic. A control group included patients with a history of anaphylaxis undergoing specific Hymenoptera immunotherapy. TPSAB1 copy numbers, BST levels, and clinical parameters were assessed and analyzed.

Results

Of 47 patients with elevated BST (≥11.4 µg/L), 93% showed increased TPSAB1 copy numbers. Individuals diagnosed with HaT displayed a BST range between 12.3 and 28.4 µg/L, with 84.1% associated with TPSAB1 duplication and 15.9% with triplication. HaT predominated in women (86.4%) and was associated with thyroid disease (27.3%). Over half had a history of anaphylaxis (54.5%), which was mainly low-grade.

Discussion

In patients with elevated BST but no mastocytosis, the most likely cause of elevated BST was an increase in the copy number of the TPSAB1 gene. A heightened risk of anaphylaxis should be considered. Further research is needed to explore the predominance of women and the emerging link with thyroid disease.
Optimizing scaffold pore size for tissue engineering: insights across various tissue types
Authors: Mukasheva Fariza , Adilova Laura , Dyussenbinov Aibek , Yernaimanova Bota , Abilev Madi , Akilbekova Dana
Published: November 2024

Scaffold porosity is a critical factor in replicating the complex in vivo microenvironment, directly influencing cellular interactions, migration, nutrient transfer, vascularization, and the formation of functional tissues. For optimal tissue formation, scaffold design must account for various parameters, including material composition, morphology, mechanical properties, and cellular compatibility. This review highlights the importance of interconnected porosity and pore size, emphasizing their impact on cellular behavior and tissue formation across several tissue engineering domains, such as skin, bone, cardiovascular, and lung tissues. Specific pore size ranges enhance scaffold functionality for different tissues: small pores (∼1–2 µm) aid epidermal cell attachment in skin regeneration, moderate pores (∼2–12 µm) support dermal migration, and larger pores (∼40–100 µm) facilitate vascular structures. For bone tissue engineering, multi-layered scaffolds with smaller pores (50–100 µm) foster cell attachment, while larger pores (200–400 µm) enhance nutrient diffusion and angiogenesis. Cardiovascular and lung tissues benefit from moderate pore sizes (∼25–60 µm) to balance cell integration and nutrient diffusion. By addressing critical design challenges and optimizing pore size distributions, this review provides insights into scaffold innovations, ultimately advancing tissue regeneration strategies.
Koala ocular disease grades are defined by chlamydial load changes and increases in Th2 immune responses
Authors: Phillips Samuel , Madden Danielle , Gillett Amber , Quigley Bonnie L. , Jelocnik Martina , Bommana Sankhya , O’Meally Denis , Timms Peter , Polkinghorne Adam
Published: November 2024

Introduction

This study employs bulk RNA sequencing, PCR, and ELISA assays to analyze the pathological factors affecting the outcomes of C. pecorum ocular infections in koalas. It investigates the immune responses and gene expression profiles associated with various stages of koala ocular chlamydiosis.

Methods

A cohort of 114 koalas from Queensland, Australia were assessed, with 47% displaying clinical signs of ocular disease. Animals were classified into three cohorts: acute active disease (G1), chronic active disease (G2), and chronic inactive disease (G3), along with subclinical Chlamydia pecorum positive (H2) and healthy (H1) cohorts.

Results

Analysis of clinical, microbiological, humoral immune and cellular immune biomarkers revealed varying chlamydial loads and anti-chlamydial IgG levels across disease grades, with a negative correlation observed between ocular chlamydial load and anti-chlamydial IgG. Koala ocular mucosa gene expression analysis from 27 koalas identified shared expression pathways across disease cohorts, with a significant upregulation of IFNγ expression and tryptophan metabolism in all disease stages.

Discussion

These findings help elucidate immune response dynamics and molecular pathways underlying koala ocular chlamydiosis, providing insights crucial for disease management strategies.
Assessment of Babesia ovis pathogenicity in goats: implications for transmission dynamics and host resistant
Authors: Ozubek Sezayi , Ulucesme Mehmet Can , Suarez Carlos E. , Bastos Reginaldo G. , Aktas Munir
Published: November 2024

Babesia ovis, commonly associated with ovine babesiosis, poses a significant threat to sheep health, often resulting in severe clinical manifestations and high mortality rates. However, the impact of B. ovis on goats has remained uncertain, prompting us to investigate its pathogenicity in caprine hosts. Experimental infections using B. ovis-infected blood inoculation and infected tick infestation, were conducted on spleen-intact (n=5) and splenectomized (n=5) goats. The experimental infection was performed using fresh blood obtained from a B. ovis-infected splenectomized sheep. One spleen-intact sheep served as a control for the experimental infection with B. ovis-infected Rhipicephalus bursa ticks. While all experimentally infected sheep (#501, #575) displayed severe clinical symptoms and high parasitemia, goats exhibited resistance, showing no significant clinical manifestations or sustained parasitemia. Notably, B. ovis was detected in two spleen-intact goats via nested PCR, prompting further investigation into their role as reservoirs for tick-borne transmission. These goats were then infested with Babesia spp.-free R. bursa larvae (0.1 gr) and adults (50 females and 50 males) for transstadial and transovarial transmission experiments respectively. Results indicated that chronically B. ovis-infected spleen-intact goats are not significant sources for maintaining the tick-borne transmission cycle of the parasite. These findings highlight the differential susceptibility of goats to B. ovis infection compared to sheep and their limited role as reservoirs for parasite transmission. Understanding the role of goats in B. ovis transmission and their resistance mechanisms can inform effective control measures and reduce economic losses in affected regions. Further research into caprine babesiosis and host immunological responses is essential to fully elucidate their possible role as reservoirs of the parasite, and underlying mechanisms of host susceptibility and parasite pathogenesis.
Causal links of human serum metabolites on the risk of prostate cancer: insights from genome-wide Mendelian randomization, single-cell RNA sequencing, and metabolic pathway analysis
Authors: Pan Renbing , Liu Jingwen , Xiao Mingjia , Sun Chuanyang , Zhu Jianyong , Wan Lijun , Xue Boxin
Published: November 2024

Background

Recently, serum metabolites have shown potential in predicting survival outcomes and may be related to the pathogenesis of prostate cancer. Nevertheless, the precise impact concerning the genetic effect of metabolites on prostate cancer risk remains obscure. In this context, we conducted a Mendelian randomization (MR) study aiming to explore the causality between genetically determined metabolites and the risk of prostate cancer.

Methods

We conducted a two-sample MR analysis aiming to identify the underlying metabolites associated with prostate cancer. Exposure information was obtained from the largest metabolome-based genome-wide association (GWAS) data containing 7,824 Europeans. Genome-wide association analysis was utilized to detect instrumental variables (IVs) for metabolites. We applied the inverse-variance weighted (IVW) approach as the primary method, and to augment the reliability and robustness of our findings, additional analysis methods encompassing weighted median, MR-Egger, and leave-one-out analysis were utilized. MR-Egger intercept test was implemented to explore the pleiotropy. Cochran’s Q test was utilized to quantify the degree of heterogeneity. Additionally, we performed metabolic pathway analysis and single-cell RNA sequencing analysis.

Results

We found that three serum metabolites were causally associated with prostate cancer after utilizing rigorous screening standards. Utilizing single nucleotide polymorphisms as IVs, a 1-SD increase in fructose was associated with 77% higher risk of prostate cancer (OR:1.77, 95%CI: 1.05-2.97, PIVW=0.031), a 1-SD increase in N1-methyl-3-pyridone-4-carboxamide was associated with 29% higher risk of prostate cancer (OR:1.29, 95%CI: 1.05-1.58, PIVW=0.017), and a 1-SD increase in 12-hydroxyeicosatetraenoate (12-HETE) was associated with 18% higher risk of prostate cancer (OR:1.18, 95%CI: 1.07-1.31, PIVW=0.0008). Metabolites that were causally linked to the risk of prostate cancer were mainly enriched in the valine, leucine and isoleucine biosynthesis pathway (P=0.026) and the nicotinate and nicotinamide metabolism pathway (P=0.048).

Conclusions

Our MR analysis provided suggestive evidence supporting the causal relationships between three identified serum metabolites and prostate cancer, necessitating further investigation to elucidate the underlying mechanisms through which these blood metabolites and metabolic pathways may impact the initiation and progression of prostate cancer.
Identification of CAPG as a potential prognostic biomarker associated with immune cell infiltration and ferroptosis in uterine corpus endometrial carcinoma
Authors: Liu Junwei , Zhu Weiqiang , Xia Lingjin , Zhu Qianxi , Mao Yanyan , Shen Yupei , Li Min , Zhang Zhaofeng , Du Jing
Published: November 2024

Introduction

Capping actin protein, gelsolin-like (CAPG) is a potential therapeutic target in various cancers. However, the potential immunotherapeutic effects and prognostic value of CAPG in uterine corpus endometrial carcinoma (UCEC) remain unclear.

Methods

The characterization, methylation effects, prognostic value, targeted miRNAs of CAPG, and the correlation of CAPG with immune cell infiltration and ferroptosis in UCEC were investigated using multiple public databases and online tools. Furtherly, we explored the potential physiological function of CAPG using EdU and Transwell migration assays, identified the cell localization and expression of CAPG and GPX4 by immunofluorescence, and detected the intracellular Fe2+ levels using a FerroOrange fluorescent probe in Ishikawa cells. Additionally, the OncoPredict package was used to analyze the potential chemotherapeutic drugs for UCEC.

Results

CAPG showed generally high expression in tumor group. The overall survival rate of the high-risk group was significantly lower than that of the low-risk group. Enrichment analysis indicated that CAPG is involved in immune-related pathways and is closely associated with the tumor microenvironment. CAPG expression levels were affected by abnormal DNA methylation and/or targeted miRNAs, infiltration levels and marker genes of various immune cells, thereby impacting immune response, ferroptosis, and patient prognosis. Ferroptosis analysis indicated that ALOX5 and VLDLR were the top CAPG-related ferroptosis markers; glutathione metabolism levels in tumor group were generally high, and decitabine was a ferroptosis inducer. CAPG-siRNA suppressed the cell proliferation and invasion, and markedly elevated the expression levels of immune-related genes IL8, TNF, TLR4 and the intracellular Fe2+ levels. CAPG co-located with GPX4 in nucleus and co-regulated ferroptosis and metabolism in Ishikawa cells. Moreover, four chemotherapy drugs showed better sensitivity to UCEC patients in the low-risk cohort.

Conclusions

CAPG may serve as a potential biomarker of UCEC owing to its role in modulating the immune response and ferroptosis, providing novel perspectives for combined immunotherapy of UCEC.
Flash glucose monitoring system help reduce the frequency of hypoglycemia and hypoglycemic fear behavior in type 1 diabetes patients
Authors: Dong Lining , Li Junxian , Hu Yanyun , Chai Ruoting , Zhu Ye , Zhu Liying , Fan Nengguang , Zhang Zhijian , Pan Jiemin , Yan Jinhua , Liu Fang
Published: November 2024

Objective

Hypoglycemia represents a serious acute complication in individuals with type 1 diabetes mellitus (T1DM). In order to more effectively identify and discriminate the occurrence of hypoglycemic events in patients with T1DM, this study aims to evaluate the impact of two distinct glucose monitoring systems—Flash Glucose Monitoring (FGM) and Continuous Glucose Monitoring (CGM)—on the management of blood glucose levels and the emotional responses associated with hypoglycemic episodes in individuals with T1DM.

Method

In this study, a total of 113 patients with type 1 diabetes mellitus were enrolled and allocated to two groups for the implementation of Glucose Monitoring Systems (GMS). The groups consisted of the FreeStyle Libre group (FGM, n=56) and the ipro2 group (CGM, n=57). Participants in both groups utilized GMS at least biannually and completed a set of three questionnaires: the Diabetes Monitoring and Treatment Satisfaction Questionnaire (DMTSQ), the Diabetes Specific Quality of Life (DQOL), and the Chinese Version of the Hypoglycemia Fear Survey II (CFHSII). Clinical data, CGM metrics, and questionnaire scores were collected at the initial visit and after a one-year follow-up period.

Results

The glucose coefficient of variation (GCV) and the standard deviation of blood glucose (SDBG) were independently associated with Time Below Range (TBR). Specifically, GCV could predict TBR ≥12%, with a cut-off point of 40.55. This yielded a specificity of 88.10% and a sensitivity of 68.18% in the overall patient population. For the FreeStyle Libre group and the iPro2 group, the cut-off points were 38.69 and 40.55, respectively, with specificities of 0.74 and 0.92, and sensitivities of 0.73 and 0.86, respectively. In the FreeStyle Libre group, where the frequency of use was greater than or equal to five times per year, the hypoglycemic episodes (time/month) and CHFSII-B scores were significantly reduced at follow-up compared to baseline (7.80 ± 10.25 vs 13.95 ± 14.87; 27.37 ± 11.05 vs 38.90 ± 21.61, respectively, all P <0.05).

Conclusion

The utilization of multiple Flash Glucose Monitoring (FGM) implementations proved to be valuable in discriminating the occurrence of hypoglycemia and mitigating the fear of hypoglycemic episodes in patients with type 1 diabetes. Within the parameters of Glucose Monitoring Systems (GMS), the glucose glycemic variability (GCV) was identified as a predictive factor for the risk of severe hypoglycemia (TBR > 12%). The optimal cut-off point for GCV was determined to be 40.55.
PSATF-6mA: an integrated learning fusion feature-encoded DNA-6 mA methylcytosine modification site recognition model based on attentional mechanisms
Authors: Kang Yanmei , Wang Hongyuan , Qin Yubo , Liu Guanlin , Yu Yi , Zhang Yongjian
Published: November 2024

DNA methylation is of crucial importance for biological genetic expression, such as biological cell differentiation and cellular tumours. The identification of DNA-6mA sites using traditional biological experimental methods requires more cumbersome steps and a large amount of time. The advent of neural network technology has facilitated the identification of 6 mA sites on cross-species DNA with enhanced efficacy. Nevertheless, the majority of contemporary neural network models for identifying 6 mA sites prioritize the design of the identification model, with comparatively limited research conducted on the statistically significant DNA sequence itself. Consequently, this paper will focus on the statistical strategy of DNA double-stranded features, utilising the multi-head self-attention mechanism in neural networks applied to DNA position probabilistic relationships. Furthermore, a new recognition model, PSATF-6 mA, will be constructed by continually adjusting the attentional tendency of feature fusion through an integrated learning framework. The experimental results, obtained through cross-validation with cross-species data, demonstrate that the PSATF-6 mA model outperforms the baseline model. The in-Matthews correlation coefficient (MCC) for the cross-species dataset of rice and m. musus genomes can reach a score of 0.982. The present model is expected to assist biologists in more accurately identifying 6 mA locus and in formulating new testable biological hypotheses.
Praziquantel and factor H recruitment differentially affect the susceptibility of Schistosoma mansoni to complement-mediated damage
Authors: van Beek Anna E. , Jeanguenat Hannah , Häberli Cécile , Pouw Richard B. , Lamers Christina , Pál Gábor , Gál Péter , Schmidt Christoph Q. , Ricklin Daniel , Keiser Jennifer
Published: November 2024

Background

Schistosomes are highly efficient evaders of human immunity, as evident by their ability to survive in human blood for years. How they protect themselves against the constant attack by a key element of innate immunity, the complement system, has remained unclear. In this study, new light is shed on the interaction between distinct life-cycle stages of Schistosoma mansoni and the human complement system.

Results

We demonstrate that schistosomula, the young stage assumed immediately after cercaria penetration of the skin, are extremely vulnerable towards complement-mediated killing as only 10-20% survive. The survival rate increases to 70% already within 30 minutes and reaches close to 100% within two hours. Pathway-specific complement inhibitors revealed the alternative pathway of complement activation as the main contributor to killing and damage of the schistosomula. Moreover, the complement regulator factor H is recruited by the schistosomula in this early stage to evade killing. Surviving parasites appear fully viable despite the ongoing complement attack, as demonstrated by the deposition of C3 fragments. However, when exposed to the widely used schistocidal drug praziquantel, the vulnerability of 24 h-old schistosomula towards complement-mediated killing is notably increased; no such effect was observed for mefloquine or oxamniquine. Similar to the younger life-cycle stages, adult worms remain under complement attack. C3 fragments were found all over the outer surface (tegument), deposited mostly on the ridges and not on the tubercles.

Conclusion

The recruitment of factor H merits more detailed studies that pinpoint the molecules involved and elucidate the novel possibilities to intercept the uncovered immune evasion therapeutically. That praziquantel and complement work in synergy is surprising and may in the future result in enhanced understanding of the drug’s mechanism of action.
Insulin-degrading enzyme regulates insulin-directed cellular autoimmunity in murine type 1 diabetes
Authors: Bessard Marie-Andrée , Moser Anna , Waeckel-Énée Emmanuelle , Lindo Vivian , Gdoura Abdelaziz , You Sylvaine , Wong F. Susan , Greer Fiona , van Endert Peter
Published: November 2024

Type 1 diabetes results from the destruction of pancreatic beta cells by autoreactive T cells. As an autoantigen with extremely high expression in beta cells, insulin triggers and sustains the autoimmune CD4+ and CD8+ T cell responses and islet inflammation. We have previously shown that deficiency for insulin-degrading enzyme (IDE), a ubiquitous cytosolic protease with very high affinity for insulin, induces endoplasmic reticulum (ER) stress and proliferation in islet cells and protects non-obese diabetic mice (NOD) from diabetes. Here we wondered whether IDE deficiency affects autoreactive CD8+ T cell responses to insulin and thereby immune pathogenesis in NOD mice. We find that Ide-/- NOD harbor fewer diabetogenic T cells and reduced numbers of CD8+ T cells recognizing the dominant autoantigen insulin and islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP). Using in vitro digestions and cellular antigen presentation assays, we show that generation of the dominant insulin epitope B15-23 involves both the proteasome and IDE. IDE deficiency attenuates MHC-I presentation of the immunodominant insulin epitope by beta cells to cognate CD8+ T cells. Consequently, Ide-/- islets display reduced susceptibility to autoimmune destruction upon grafting, and to killing by insulin-specific CD8+ T cells. Moreover, Ide-/- mice are partly resistant to disease transfer by CD8+ T cells specific for insulin but not for IGRP. Thus, IDE has a dual role in beta cells, regulating ER stress and proliferation while at the same time promoting insulin-directed autoreactive CD8+ T cell responses.
Neutrophils enhance the clearance of systemic amyloid deposits in a murine amyloidoma model
Authors: Hancock Trevor J. , Vlasyuk Marina , Foster James S. , Macy Sallie , Wooliver Daniel C. , Balachandran Manasi , Williams Angela D. , Martin Emily B. , Kennel Stephen J. , Heidel Eric R. , Wall Jonathan S. , Jackson Joseph W.
Published: November 2024

Introduction

Amyloid-specific antibodies have been shown to opsonize and enhance amyloid clearance in systemic amyloidosis mouse models. However, the immunological mechanisms by which amyloid is removed have not been clearly defined. Previous reports from preclinical in vivo studies suggest polymorphonuclear cells (i.e., neutrophils) can affect amyloid removal. Therefore, we sought to analyze how neutrophils may contribute to the clearance of human AL amyloid extracts, using a murine amyloidoma model.

Methods

Immunocompromised nude mice injected subcutaneously with patient-derived AL amyloid extract (generating a localized “amyloidoma”) were used to circumvent confounding factors contributed by the adaptive immune system and served as the model system. Two representative AL amyloid extracts were used, ALλ(CLA), which is refractory to clearance, and ALκ(TAL), which is readily cleared in mice. Neutrophil recruitment to the amyloid masses, cellular activation, and propensity to engulf amyloid were assessed.

Results

Immunophenotyping of amyloidomas from animals implanted with 2 mg of either ALλ or ALκ revealed that more neutrophils were recruited to ALκ amyloid masses as compared to the ALλ material, which was generally devoid of neutrophils. Ex vivo analyses indicated neutrophils do not efficiently phagocytose amyloid directly. However, histological evaluation of the ALκ amyloidoma revealed the abundant presence of neutrophil extracellular traps, which were absent in the ALλ amyloidomas. Using neutrophil depletion experiments in mice, we determined that mice devoid of neutrophils cleared the human amyloid lesions less efficiently. Moreover, mice devoid of neutrophils also had significantly reduced intra-amyloid expression of inflammatory cytokines.

Discussion

Neutrophils may not directly mediate amyloid clearance through phagocytosis; however, these cells can be stimulated by the amyloid and may function to facilitate phagocytosis and amyloid clearance by professional phagocytes (e.g., macrophages).
Applications of single-cell RNA sequencing in rheumatoid arthritis
Authors: Figueiredo Marxa L.
Published: November 2024

Single cell RNA sequencing (scRNA-seq) is a relatively new technology that provides an unprecedented, detailed view of cellular heterogeneity and function by delineating the transcriptomic difference among individual cells. This will allow for mapping of cell-type-specific signaling during physiological and pathological processes, to build highly specific models of cellular signaling networks between the many discrete clusters that are present. This technology therefore provides a powerful approach to dissecting the cellular and molecular mechanisms that contribute to autoimmune diseases, including rheumatoid arthritis (RA). scRNA-seq can offer valuable insights into RA unique cellular states and transitions, potentially enabling development of novel drug targets. However, some challenges that still limit its mainstream utilization and include higher costs, a lower sensitivity for low-abundance transcripts, and a relatively complex data analysis workflow relative to bulk or traditional RNA-seq. This minireview explores the emerging application of scRNA-seq in RA research, highlighting its role in producing important insights that can help pave the way for innovative and more effective therapeutic strategies.
The established of a machine learning model for predicting the efficacy of adjuvant interferon alpha1b in patients with advanced melanoma
Authors: Jiang Linhan , Su Ke , Wang Jing , Lin Yitong , Zhao Xianya , Zhang Hengxiang , Liu Yu
Published: November 2024

Background

Interferon-alpha1b (IFN-α1b) has shown remarkable therapeutic potential as adjuvant therapy for melanoma. This study aimed to develop five machine learning models to evaluate the efficacy of postoperative IFN-α1b in patients with advanced melanoma.

Methods

We retrospectively analyzed 113 patients with the American Joint Committee on Cancer (AJCC) stage III-IV melanoma who received postoperative IFN-α1b therapy between July 2009 and February 2024. Recurrence-free survival (RFS) and overall survival (OS) were assessed using Kaplan-Meier analysis. Five machine learning models (Decision Tree, Cox Proportional Hazards, Random Forest, Support Vector Machine, and LASSO regression) were developed and compared for their capacity to predict the outcomes of patients. Model performance was evaluated using concordance index (C-index), time-dependent receiver operating characteristic (ROC) curves, and decision curve analysis.

Results

The 1-year, 2-year, and 3-year RFS rates were 71.10%, 43.10%, and 31.10%, respectively. For OS, the 1-year, 2-year, and 3-year OS rates were 99.10%, 82.30%, and 75.00%, respectively. The Decision Tree (DT) model demonstrated superior predictive performance with the highest C-index of 0.792. Time-dependent ROC analysis for predicting 1-, 2-, and 3-year RFS based on the DT model is 0.77, 0.79 and 0.76, respectively. Serum albumin emerged as the important predictor of RFS.

Conclusions

Our study demonstrates the considerable efficacy DT model for predicting the efficacy of adjuvant IFN-α1b in patients with advanced melanoma. Serum albumin was identified as a key predictive factor of the treatment efficacy.
Lactiplantibacillus plantarum inhibited the growth of primary liver cancer by inducing early apoptosis and senescence, in vitro
Authors: Duduyemi Oladimeji Paul , Potapenko Kateryna , Limanska Nataliia , Kotsyuda Sofiya , Petriv Nataliia , Suo Huizhen , Gudzenko Tetyana , Ivanytsia Volodymyr , Yevsa Tetyana
Published: November 2024

Primary liver cancer (PLC), comprising hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), is a severe form of cancer associated with a high mortality and morbidity rate and increasing incidence worldwide. Current treatment options are limited and chemotherapeutics demonstrate strong side effects. New therapies are highly required. Lactobacilli represent the most diverse lactic acid-producing bacteria group and a prominent example of probiotics. Several studies have highlighted the anticancer efficacy of probiotics, especially of Lactiplantibacillus plantarum. However, there are limited studies on its activity on two PLC types, hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA). This study evaluated the inhibitory mechanism and properties of L. plantarum ONU 12 (Lp 12) and L. plantarum ONU 355 (Lp 355), isolated from grapes in Ukraine and France, in murine PLC cell lines, in vitro. Strain Lacticaseibacillus casei ATCC 393 (Lc 393) has been taken for a direct comparison, as the most studied probiotic strain. The three Lactobacillus species were used in three forms: as live and heat-killed suspensions, and as sonicated extracts, and tested either as a monotherapy or in combination with standard chemotherapeutics (sorafenib for HCC and gemcitabine for CCA). Cell proliferation and viability were assessed via crystal violet staining assay and cell counting kit-8 assay. The induction of senescence was investigated by senescence-associated β-galactosidase assay. Fluorescence-activated cell sorting analysis was used to determine the apoptotic mechanism behind the inhibitory property of lactobacilli. The results showed that the live suspensions and sonicated extracts of Lp 12, Lp 355, and Lc 393 demonstrated inhibitory properties in CCA and HCC cells after 48 h of incubation. In combinations with standard chemotherapeutics, lactobacilli treatments have shown strong synergistic effects. The combination therapy allowed to reduce the chemotherapeutic doses of gemcitabine from 50 μM to 0.1 and 0.05 μM and sorafenib from 13.8 μM to 6.9 and 3.45 μM. Successful treatment regimes induced early apoptosis and cellular senescence in PLC, as the mechanism of inhibition. Heat-killed suspensions showed no inhibitory effect in none of the cell lines. Both strains, Lp 12 and Lp 355, showed successful results and need further testing in vivo, using autochthonous HCC and CCA models.
Characterization of the T-cell receptor repertoire associated with lymph node metastasis in colorectal cancer
Authors: Zhen Ya’nan , Wang Hong , Jiang Runze , Wang Fang , Chen Cunbao , Xu Zhongfa , Xiao Ruixue
Published: November 2024

Purpose

Colorectal cancer (CRC) is a leading cause of cancer-related mortality worldwide, with lymph node (LN) metastasis playing a pivotal role in disease progression. This study aimed to explore the T-cell receptor (TCR) repertoire among CRC patients, distinguishing those with LN metastasis from those without, in order to uncover potential biomarkers for predicting metastasis.

Methods

We analyzed the TCR repertoire in CRC patients with and without LN metastasis. A classification model utilizing random forest analysis was developed to assess the predictive potential of the TCR repertoire.

Results

The findings demonstrated a significant increase in the number of V-J combinations and immune CDR3 sequences in patients with LN metastasis compared to the control group. The classification model achieved high accuracy in differentiating patients with LN metastasis, with AUC values ranging from 0.514 to 0.794. Specific V-J combinations and CDR3 sequences were identified as significant predictors of the model’s predictive accuracy.

Conclusion

These results suggest that the TCR repertoire is altered in CRC patients exhibiting LN metastasis, potentially influencing disease progression. This study highlights the importance of TCR repertoire analysis as a non-invasive biomarker for predicting LN metastasis in CRC patients.
An insight to PDAC tumor heterogeneity across pancreatic subregions using computed tomography images
Authors: Javed Sehrish , Qureshi Touseef Ahmad , Wang Lixia , Azab Linda , Gaddam Srinivas , Pandol Stephen J. , Li Debiao
Published: November 2024

Pancreatic Ductal Adenocarcinoma (PDAC) is an exceptionally deadly form of pancreatic cancer with an extremely low survival rate. From diagnosis to treatment, PDAC is highly challenging to manage. Studies have demonstrated that PDAC tumors in distinct regions of the pancreas exhibit unique characteristics, influencing symptoms, treatment responses, and survival rates. Gaining insight into the heterogeneity of PDAC tumors based on their location in the pancreas can significantly enhance overall management of PDAC. Previous studies have explored PDAC tumor heterogeneity across pancreatic subregions based on their genetic and molecular profiles through biopsy-based histologic assessment. However, biopsy examinations are highly invasive and impractical for large populations. Abdominal imaging, such as Computed Tomography (CT) offers a completely non-invasive means to evaluate PDAC tumor heterogeneity across pancreatic subregions and an opportunity to correlate image feature of tumors with treatment outcome and monitoring. In this study, we explored the inter-tumor heterogeneity in PDAC tumors across three primary pancreatic subregions: the head, body, and tail. Utilizing contrast-enhanced abdominal CT scans and a thorough radiomic analysis of PDAC tumors, several morphological and textural tumor features were identified to be notably different between tumors in the head and those in the body and tail regions. To validate the significance of the identified features, a machine learning ML model was trained to automatically classify PDAC tumors into their respective regions i.e. head or body/tail subregion using their CT features. The study involved 200 CT abdominal scans, with 100 used for radiomic analysis and model training, and the remaining 100 for model testing. The ML model achieved an average classification accuracy, sensitivity, and specificity of 87%, 86%, and 88% on the testing scans respectively. Evaluating the heterogeneity of PDAC tumors across pancreatic subregions provides valuable insights into tumor composition and has the potential to enhance diagnosis and personalize treatment based on tumor characteristics and location.