bluuebunny/crossref_metadata_2025 huggingface dataset:
Tác động của quản trị nhân sự số đến hiệu quả kinh doanh của doanh nghiệp Việt Nam
Authors: Nguyễn Thị Ngọc Duyên
Published: June 2024

Bài viết nghiên cứu tác động của quản trị nhân sự (QTNS) số đối với hiệu quả kinh doanh (HQKD) của các doanh nghiệp Việt Nam. Phương pháp định lượng được sử dụng bao gồm đo lường thang đo, phân tích nhân tố và phân tích hồi quy dựa trên việc chọn mẫu thuận tiện với số quan sát thu về là 271. Kết quả cho thấy bốn yếu tố cơ bản của quản trị nguồn nhân lực được cải thiện nhờ chuyển đổi số có ảnh hưởng cùng chiều đến HQKD của các doanh nghiệp Việt Nam, bao gồm: nâng cao tuyển dụng nhân sự số, nâng cao quản lý công việc số, nâng cao trình độ nhân sự số và nâng cao quản trị năng suất nhân sự số. Tác giả gợi ý một vài giải pháp để phát triển QTNS số nhằm nâng cao hiệu suất của các doanh nghiệp.
The Influence of Social Media as a Tourism Marketing Tool in Negros Oriental, Philippines
Authors: Tayco Ryan , Tubog Millard Vaughn , Zamora Glennen
Published: June 2024

The study aimed to determine the influence of social media as a tourism marketing tool for Negros Oriental as a tourist destination. Utilizing a descriptive method and a correlational technique, this research focused on both local and foreign tourists visiting Negros Oriental. A total of 392 tourists were selected through convenience sampling to participate as respondents. Results indicate that the majority of respondents are female, unmarried, aged between 18 and 30, and heavily rely on social media for information, particularly when planning activities and trips. A significant portion of respondents are college-educated Filipinos, who spend an average of 4 hours and 15 minutes daily on social media. Most respondents are employed and use social media for both professional and personal purposes. Findings reveal that most travelers visit Negros Oriental for relaxation and extensively use smartphones for travel-related purposes. Facebook emerged as the most commonly used platform, significantly influencing travel decisions and planning. Socio-demographic factors such as age, gender, civil status, educational level, and occupation were found to influence social media usage patterns and travel decisions. The study concludes that social media is an effective tourism marketing tool, capable of influencing tourists' decisions regarding their visits to tourist destinations.
Post-Truth, a new Phenomenon, or an already existing one: An Investigation into the Phenomenon of Post-Truth
Authors: Ukpaka Paschal
Published: June 2024

The phenomenon of post-truth has its roots in the timeless connection between lies and politics, but in the early 21st century, certain conditions has allowed this relation between lies and politics to evolve into a new form, which is the phenomenon of “post-truth” which has become part of the contemporary political vocabulary. The article gives an account of this relation as described by Hannah Arendt, traces the specific changes this relation has undergone, and explores the historical conditions that precipitated this evolution, namely social media and its role in the decline of institutions that traditionally safeguarded truth. Finally, it poses the question of what solutions are possible. For example, are “facts” as stubborn as Arendt suggests?
LA DILIGENCIA DEBIDA OBLIGATORIA EN DERECHOS HUMANOS: AVANCES Y DESAFÍOS
Authors: Iglesias Márquez Daniel , Del Valle Calzada Estrella , Chiara Marullo Maria
Published: June 2024

De acuerdo con los Principios Rectores de las Naciones Unidas sobre empresas y derechos humanos, todas las empresas tienen la responsabilidad de respetar los derechos humanos. Esta responsabilidad va más allá del mero hecho de abstenerse de infringir los derechos humanos de terceros, sino que requiere la adopción de medidas proactivas para prevenir y reparar los efectos perjudiciales de sus actividades. El mecanismo prescrito en los Principios Rectores para que las empresas pongan en práctica su responsabilidad de respetar es la diligencia debida en derechos humanos, que constituye un proceso continuo de gestión mediante el cual una empresa aborda las consecuencias negativas que pueda generar para los derechos humanos en el contexto de sus operaciones y productos y en todas sus relaciones comerciales. No obstante, ante la escasa implementación voluntaria de este proceso, recientemente han emergido o están en elaboración marcos jurídicos de diligencia debida obligatoria. En Europa, hay un impulso particular hacia la creación de este tipo de normas, con leyes ya adoptadas en países como Francia, Alemania, los Países Bajos y Noruega. Así, esta obra colectiva pretende ofrecer una panorámica de conjunto de la debida diligencia obligatoria en derechos humanos, desde el análisis jurídico preciso del contexto normativo, integrando propuestas constructivas hacia el futuro que está por venir en Europa y en América Latina, y hasta incluso abarcar el estudio de la casuística más reciente y relevante en la materia.
LAS EMPRESAS ESTATALES PETROLERAS: LA VIABILIDAD DE LA INMUNIDAD DEL ESTADO EN CASOS DE VULNERACIÓN DE LOS DERECHOS HUMANOS
Authors: Elizalde Carranza Miguel
Published: June 2024

De acuerdo con los Principios Rectores de las Naciones Unidas sobre empresas y derechos humanos, todas las empresas tienen la responsabilidad de respetar los derechos humanos. Esta responsabilidad va más allá del mero hecho de abstenerse de infringir los derechos humanos de terceros, sino que requiere la adopción de medidas proactivas para prevenir y reparar los efectos perjudiciales de sus actividades. El mecanismo prescrito en los Principios Rectores para que las empresas pongan en práctica su responsabilidad de respetar es la diligencia debida en derechos humanos, que constituye un proceso continuo de gestión mediante el cual una empresa aborda las consecuencias negativas que pueda generar para los derechos humanos en el contexto de sus operaciones y productos y en todas sus relaciones comerciales. No obstante, ante la escasa implementación voluntaria de este proceso, recientemente han emergido o están en elaboración marcos jurídicos de diligencia debida obligatoria. En Europa, hay un impulso particular hacia la creación de este tipo de normas, con leyes ya adoptadas en países como Francia, Alemania, los Países Bajos y Noruega. Así, esta obra colectiva pretende ofrecer una panorámica de conjunto de la debida diligencia obligatoria en derechos humanos, desde el análisis jurídico preciso del contexto normativo, integrando propuestas constructivas hacia el futuro que está por venir en Europa y en América Latina, y hasta incluso abarcar el estudio de la casuística más reciente y relevante en la materia.
TALABALARDA MUSIQA TURIZMI VOSITASIDA TOLERANTLIKNI RIVOJLANTIRISHDA TARBIYAVIY TADBIRLARNING O‘RNI
Authors: Aziza ABDUMANNATOVA
Published: June 2024

Maqolada bo`lajak musiqa o`qituvchilarida musiqa turizmi vositasi orqali tolerantlikni rivojlantirish, tolerantlikni rivojlantirishda tarbiyaviy tadbirlarning o`rni haqidagi ma’lumotlar bayon etilgan.
TOSHKENT VILOYATIDA NOZOGEOGRAFIK VAZIYATGA TA’SIR ETUVCHI OMILLAR
Authors: Komilaxon XUSANOVA
Published: June 2024

Ushbu maqolada Toshkent viloyati nozogeografik vaziyatiga qanday omillar ta’sir qilishi va ularning tahlili berilgan. Viloyatning aholi kasallanish ko‘rsatkichlarining ayrim jihatlari yoritilgan. Nozogeografik vaziyatga salbiy ta’sir etuvchi atmosfera havosining ifloslanishi qay holatda ekanligi tumanlar kesimida ochib berilgan.
THE IDEA OF MAQASYID SYARIAH ACCORDING TO AL-SYATIBI AND ITS IMPLEMENTATION OF THE ISLAMIC ECONOMY
Authors: Rijaludawa Wawa , Yanti Nurniati
Published: June 2024

Bermula dari tujuan agama Islam adalah untuk tercapainya kemaslahatan, salah satunya adalah kemasalhatan yang bersifat dharuriyat yang tercakup dalam maqasid Shariah, menjadikan penelitian ini sebagai pembahasan terkait dengan praktik maqasid shariah dalam dunia ekonomi dalam perspektif Al Syatibi. Metode peneltian yang digunakan adalah library research. Hasil penelitian menunjukan, konsep berekonomi sesuai syariat adalah bagian penting dari kebutuhan manusia. Hal ini menyesuaikan dengan Indeks pemberdayaan ekonomi masyarakat dalam memenuhi kesejahteraannya meliputi pendapatan, konsumsi, keadaan hidup, fasilitas perumahan, kesehatan rumah tangga, kualitas pendidikan keluarga, kemudahan anak memasuki jenjang pendidikan, dan perasaan aman bebas dari intervensi kriminal. Sehingga Ekonomi Syariah bagian dari alternatif pemecahan masalah kebutuhan manusia terutama pada hal-hal tersebut yang dimaksud.
Taking up Residence in a Historic Town Hall Building
Authors: Romme Larsen Birgitte
Published: June 2024

N/A
Impacto del cambio climático en la hidrología de regiones criohidrológicas: una revisión sistemática
Authors: Machado Valdivia Amanda , Sotolongo Díaz Dunia
Published: June 2024

Las regiones criohidrológicas (RC), caracterizadas por su presencia de hielo y nieve, enfrentan desafíos crecientes debido al cambio climático. Este estudio aborda la compleja interacción entre el cambio climático y la hidrología en estas áreas cruciales. Objetivo: analizar tendencias, brechas de conocimiento y direcciones futuras de investigación. Metodología: la metodología fue cualitativa, ya que implica una revisión sistemática de la literatura científica, identificando patrones y desafíos. Desarrollo: los resultados revelan tendencias significativas en la influencia del cambio climático en las RC, destacando la importancia de comprender las percepciones y capacidades adaptativas de las comunidades. Se identificaron brechas de conocimiento en la evaluación de la precisión de modelos climáticos y la necesidad de caracterizar detalladamente los efectos de las emisiones de gases de efecto invernadero. Conclusión: las metodologías utilizadas, desde modelos climáticos globales hasta herramientas de evaluación de suelos, ofrecen perspectivas valiosas, pero se enfrentan a desafíos como la incertidumbre y los sesgos sistemáticos.
Capital social y empoderamiento: estrategias de trabajo social en comunidades rurales
Authors: Rivas de García Brenda Lisseth
Published: June 2024

En las comunidades rurales, enfrentar retos como la pobreza, la desigualdad y el acceso limitado a servicios básicos requiere de estrategias que fomenten el empoderamiento y mejoren la calidad de vida. El trabajo social comunitario, apoyándose en la capacidad intrínseca de las comunidades para superar sus problemas con las herramientas adecuadas, emerge como un método clave para inducir cambios positivos. Este artículo se propuso examinar cómo el trabajo social comunitario puede empoderar a estas comunidades, potenciando su desarrollo y bienestar. Para ello, se desarrolló un estudio con enfoque cualitativo y empleando la revisión sistemática, como principal recurso metodológico. Los resultados revelan que las estrategias de empoderamiento, el fortalecimiento de redes de apoyo y el fomento del capital social son fundamentales para lograr comunidades rurales más resilientes y autosuficientes. Se concluye que el trabajo social comunitario desempeña un papel esencial en la promoción de la justicia social y el bienestar, demostrando ser una herramienta poderosa para el empoderamiento de las comunidades rurales, permitiendo que trasciendan sus desafíos y mejoren su calidad de vida de manera significativa.
Gestión de gobierno basado en el conocimiento, la ciencia, la tecnología y la innovación
Authors: Díaz Páez Deysy , Álvarez Díaz Dianelys , Solano Hernández Cirilo , Cabrera Miranda José Ramón , Mesa Sotolongo Sara
Published: June 2024

El municipio de Los Palacios ha enfrentado desafíos significativos en términos de desarrollo económico y gestión de recursos, lo cual ha exigido una revisión profunda de su enfoque hacia la autonomía municipal y la sostenibilidad. En respuesta a estos desafíos, el objetivo de este artículo es analizar cómo la implementación de una gestión basada en la ciencia y la innovación puede transformar la gestión pública local y promover el desarrollo sostenible. Para ello, se adoptó una metodología cualitativa que incluye el análisis de documentos y estudios de caso específicos dentro del municipio. Los resultados indican que la adopción de prácticas innovadoras y el fortalecimiento de la cultura organizacional han mejorado significativamente la eficiencia de los procesos municipales y la calidad de vida de los ciudadanos. La conclusión más relevante es que una gestión pública local efectiva, apoyada en la ciencia y la innovación, no solo optimiza recursos, sino que también fomenta una mayor participación ciudadana y una planificación estratégica más efectiva, elementos clave para el desarrollo local sostenible.
Epistemología de izquierda y ética de derecha en las universidades públicas
Authors: Alarcón Osorio Daniel , Gonzales Soria Mauricio Bahid
Published: June 2024

La educación superior atraviesa crisis histórica y cambio de época. Crisis cuyas características son pérdida en la visión de que la educación tiene y deber ser un proceso, en lugar de un producto. Esta crisis de la educación superior tiene consecuencias negativas en la sociedad, puesto que reduce oportunidades de desarrollo de los estudiantes y el progreso de la sociedad en su conjunto. Analizar la crisis de la educación superior e identificar los factores junto con los impactos que contiene, permite proponer recomendaciones específicas para enfrentar y superar la crisis.
Preoperative embolization and en bloc resection of a metastatic pheochromocytoma of the cervical spine
Authors: Singh Aman , Santangelo Gabrielle , Ellens Nathaniel , Kohli Gurkirat , Pranaat Robert , Bender Matthew T.
Published: June 2024

This is a unique case of metastatic pheochromocytoma of the cervical spine treated with preoperative embolization and subsequent en bloc resection. A 65-year-old man with metastatic pheochromocytoma presented with two weeks of worsening neck pain, left arm and leg weakness and paresthesia, and urinary incontinence. Magnetic resonance imaging showed a metastatic osseous lesion at C6 with severe stenosis and spinal cord compression. The patient underwent successful preoperative angiographic embolization with a liquid embolic agent followed by C5-C7 laminectomy, en bloc tumor resection, and C3-T2 posterior spinal fusion. Six weeks postoperatively, the patient reported improving strength and resolving neck pain and paresthesias. While there is no standard paradigm for the treatment of metastatic pheochromocytomas of the cervical spine, preoperative embolization may minimize intraoperative blood loss and hemodynamic instability during subsequent surgical resection.
Mechanism of boundary bubble drag reduction of Couette flow in nano-confined domain
Authors: Zhang Peng , Zhang Yan-Ru , Zhang Fu-Jian , Liu Zhen , Zhang Zhong-Qiang ,   School of Mechanical Engineering, Jiangsu University, Zhenjiang 212013, China,   School of Ship and Ocean Engineering, Jiangsu University of Science and Technology, Zhenjiang 212003, China,   State Key Laboratory of Structural Analysis of Industrial Equipment, Dalian University of Technology, Dalian 116024, China
Published: June 2024

Bubble drag reduction technology is of great significance in improving the propulsion efficiency of underwater vehicle and reducing the comprehensive energy consumption during navigation. Bubble drag reduction is a highly effective method of reducing the frictional resistance encountered by large ships and underwater vehicles during navigation. It exhibits excellent stability in drag reduction, and has advantages such as environmental friendliness, adaptability to various flow environments, and suitability for all underwater components of ships. Therefore, it is greatly significant to conduct in-depth research on bubble drag reduction and its underlying mechanism. In this work, the flow characteristics and the boundary bubble drag reduction mechanism of gas-liquid Couette flow in parallel wall nanochannels are studied by molecular dynamics method, and the influences of surface wettability, wall roughness, and gas concentration on boundary slip velocity and bubble drag reduction effect are analyzed. The results indicate that the bubble drag reduction effect is enhanced with the increase of boundary slip velocity. In the gas-liquid two-phase flow region, with the increase of shear velocity, the lateral deformation of boundary adsorbed bubble and boundary slip velocity increase, thus enhancing the bubble drag reduction effect. The increase of solid-gas interaction strength and gas concentration can lead to the enrichment of gas atoms near the wall, improve the bubble spreading characteristics on the wall, and thus increase the slip velocity of the solid-liquid interface. The wall roughness can change the spreading characteristics of bubble, affect the boundary slip velocity, and then change the drag reduction effect of the fluid-solid interface. As the rib height increases, gas atoms accumulate in the grooves between ribs and the adsorption quantity of gas atoms on the upper surface of the rib decreases, which leads to the decrease of the boundary slip velocity of the solid-liquid interface and ultimately reduces the drag reduction effect. The research results will provide important theoretical guidance for implementing the boundary drag reduction technology in large ships and underwater vehicles.
Spatial Transcriptomics of Meningeal Inflammation Reveals Variable Penetrance of Inflammatory Gene Signatures into Adjacent Brain Parenchyma
Authors: Gadani Sachin P. , Singh Saumitra , Kim Sophia , Hu Jingwen , Smith Matthew D. , Calabresi Peter A. , Bhargava Pavan
Published: June 2024

While modern high efficacy disease modifying therapies have revolutionized the treatment of relapsing-remitting multiple sclerosis, they are less effective at controlling progressive forms of the disease. Meningeal inflammation is a recognized risk factor for cortical grey matter pathology which can result in disabling symptoms such as cognitive impairment and depression, but the mechanisms linking meningeal inflammation and grey matter pathology remain unclear. Here, we performed MRI-guided spatial transcriptomics in a mouse model of autoimmune meningeal inflammation to characterize the transcriptional signature in areas of meningeal inflammation and the underlying brain parenchyma. We found broadly increased activity of inflammatory signaling pathways at sites of meningeal inflammation, but only a subset of these pathways active in the adjacent brain parenchyma. Sub-clustering of regions adjacent to meningeal inflammation revealed the subset of immune programs induced in brain parenchyma, notably complement signaling and antigen processing/presentation. Trajectory gene and gene set modeling analysis confirmed variable penetration of immune signatures originating from meningeal inflammation into the adjacent brain tissue. This work contributes a valuable data resource to the field, provides the first detailed spatial transcriptomic characterization in a model of meningeal inflammation, and highlights several candidate pathways in the pathogenesis of grey matter pathology.
Transcriptional immune suppression and up-regulation of double-stranded DNA damage and repair repertoires in ecDNA-containing tumors
Authors: Lin Miin S , Jo Se-Young , Luebeck Jens , Chang Howard Y , Wu Sihan , Mischel Paul S , Bafna Vineet
Published: June 2024

Extrachromosomal DNA is a common cause of oncogene amplification in cancer. The non-chromosomal inheritance of ecDNA enables tumors to rapidly evolve, contributing to treatment resistance and poor outcome for patients. The transcriptional context in which ecDNAs arise and progress, including chromosomally-driven transcription, is incompletely understood. We examined gene expression patterns of 870 tumors of varied histological types, to identify transcriptional correlates of ecDNA. Here, we show that ecDNA-containing tumors impact four major biological processes. Specifically, ecDNA-containing tumors up-regulate DNA damage and repair, cell cycle control, and mitotic processes, but down-regulate global immune regulation pathways. Taken together, these results suggest profound alterations in gene regulation in ecDNA-containing tumors, shedding light on molecular processes that give rise to their development and progression.
Fine-tuning spatial-temporal dynamics and surface receptor expression support plasma cell-intrinsic longevity
Authors: Jing Zhixin , Galbo Phillip , Ovando Luis , Demouth Megan , Welte Skylar , Park Rosa , Chandran Kartik , Wu Yinghao , MacCarthy Thomas , Zheng Deyou , Fooksman David
Published: June 2024

Durable serological memory following vaccination is critically dependent on the production and survival of long-lived plasma cells (LLPCs). Yet, the factors that control LLPC specification and survival remain poorly resolved. Using intravital two-photon imaging, we find that in contrast to most plasma cells (PCs) in the bone marrow (BM), LLPCs are uniquely sessile and organized into clusters that are dependent on APRIL, an important survival factor. Using deep, bulk RNA sequencing, and surface protein flow-based phenotyping, we find that LLPCs express a unique transcriptome and phenotype compared to bulk PCs, fine-tuning expression of key cell surface molecules, CD93, CD81, CXCR4, CD326, CD44, and CD48, important for adhesion and homing. Conditional deletion of Cxcr4 in PCs following immunization leads to rapid mobilization from the BM, reduced survival of antigen-specific PCs, and ultimately accelerated decay of antibody titer. In naïve mice, the endogenous LLPCs BCR repertoire exhibits reduced diversity, reduced somatic mutations, and increased public clones and IgM isotypes, particularly in young mice, suggesting LLPC specification is non-random. As mice age, the BM PC compartment becomes enriched in LLPCs, which may outcompete and limit entry of new PCs into the LLPC niche and pool.
Diffusive lensing as a mechanism of intracellular transport and compartmentalization
Authors: Raja Venkatesh Achuthan , Le Kathy H , Weld David M , Brandman Onn
Published: June 2024

While inhomogeneous diffusivity has been identified as a ubiquitous feature of the cellular interior, its implications for particle mobility and concentration at different length scales remain largely unexplored. In this work, we use agent-based simulations of diffusion to investigate how heterogeneous diffusivity affects the movement and concentration of diffusing particles. We propose that a nonequilibrium mode of membrane-less compartmentalization arising from the convergence of diffusive trajectories into low-diffusive sinks, which we call ‘diffusive lensing,’ is relevant for living systems. Our work highlights the phenomenon of diffusive lensing as a potentially key driver of mesoscale dynamics in the cytoplasm, with possible far-reaching implications for biochemical processes.
Liver microRNA transcriptome reveals miR-182 as link between type 2 diabetes and fatty liver disease in obesity
Authors: Krause Christin , Britsemmer Jan H. , Bernecker Miriam , Molenaar Anna , Taege Natalie , Lopez-Alcantara Nuria , Geißler Cathleen , Kaehler Meike , Iben Katharina , Judycka Anna , Wagner Jonas , Wolter Stefan , Mann Oliver , Pfluger Paul T. , Cascorbi Ingolf , Lehnert Hendrik , Stemmer Kerstin , Schriever Sonja C. , Kirchner Henriette
Published: June 2024

The development of obesity-associated comorbidities such as type 2 diabetes (T2D) and hepatic steatosis has been linked to selected microRNAs in individual studies; however, an unbiased genome-wide approach to map T2D induced changes in the miRNAs landscape in human liver samples, and a subsequent robust identification and validation of target genes is still missing.Liver biopsies from age- and gender-matched obese individuals with (n=20) or without (n=20) T2D were used for microRNA microarray analysis. The candidate microRNA and target genes were validated in 85 human liver samples, and subsequently mechanistically characterized in hepatic cells as well as by dietary interventions and hepatic overexpression in mice.Here we present the human hepatic microRNA transcriptome of type 2 diabetes in liver biopsies and use a novel seed prediction tool to robustly identify microRNA target genes, which were then validated in a unique cohort of 85 human livers. Subsequent mouse studies identified a distinct signature of T2D-associated miRNAs, partly conserved in both species. Of those, human-murine miR-182-5p was the most associated to whole-body glucose homeostasis and hepatic lipid metabolism. Its target gene
LRP6
was consistently lower expressed in livers of obese T2D humans and mice as well as under conditions of miR-182-5p overexpression. Weight loss in obese mice decreased hepatic miR-182-5p and restored
Lrp6
expression and other miR-182-5p target genes. Hepatic overexpression of miR-182-5p in mice rapidly decreased LRP6 protein levels and increased liver triglycerides and fasting insulin under obesogenic conditions after only seven days.By mapping the hepatic miRNA-transcriptome of type 2 diabetic obese subjects, validating conserved miRNAs in diet-induced mice, and establishing a novel miRNA prediction tool, we provide a robust and unique resource that will pave the way for future studies in the field. As proof of concept, we revealed that the repression of
LRP6
by miR-182-5p, which promotes lipogenesis and impairs glucose homeostasis, provides a novel mechanistic link between T2D and non-alcoholic fatty liver disease, and demonstrate in vivo that miR-182-5p can serve as a future drug target for the treatment of obesity-driven hepatic steatosis.
Tumor Purity-Related Genes for Predicting the Prognosis and Drug Sensitivity of DLBCL Patients
Authors: Ye Zhenbang , Huang Ning , Fu Yongliang , Tian Rongle , Wang Liming , Huang Wenting
Published: June 2024

Diffuse large B-cell lymphoma (DLBCL) is the predominant type of malignant B-cell lymphoma. Although various treatments have been developed, the limited efficacy calls for more and further exploration of its characteristics.Datasets from Gene Expression Omnibus (GEO) database were used for identifying the tumor purity of DLBCL. Survival analysis was employed for analyzing the prognosis of DLBCL patients. Immunohistochemistry was conducted to detect the important factor that influenced the prognosis. Drug sensitive prediction was performed to evaluate the value of the constructed model.VCAN, CD3G and C1QB were identified as three key genes that impacted the outcome of DLBCL patients both in GEO datasets and samples from our center. Among them, VCAN and CD3G+ T cells were correlated with favorable prognosis, and C1QB was correlated with worse prognosis. The ratio of CD68+ macrophages and CD8+ T cells was associated with better prognosis. In addition, CD3G+ T cells ratio was significantly correlated with CD68+ macrophages, CD4+ T cells and CD8+ T cells ratio, indicating it could play an important role in the anti-tumor immunity in DLBCL. The riskScore model constructed based on the RNASeq data of VCAN, C1QB and CD3G work well in predicting the prognosis and drug sensitivity.VCAN, CD3G and C1QB were three key genes that influenced the tumor purity of DLBCL, and could also exert certain impact on drug sensitivity and prognosis of DLBCL patients.
Mapping responses to focal injections of bicuculline in the lateral parafacial region identifies core regions for maximal generation of active expiration
Authors: Pisanski Annette , Prostebby Mitchell , Dickson Clayton T. , Pagliardini Silvia
Published: June 2024

The lateral parafacial area (pFL) is a crucial region involved in respiratory control, particularly in generating active expiration through an expiratory oscillatory network. Active expiration involves rhythmic abdominal (ABD) muscle contractions during late- expiration, increasing ventilation during elevated respiratory demands. The precise anatomical location of the expiratory oscillator within the ventral medulla’s rostro-caudal axis is debated. While some studies point to the caudal tip of the facial nucleus (VIIc) as the oscillator’s core, others suggest more rostral areas. Our study employed bicuculline (a GABA-A receptor antagonist) injections at various pFL sites (-0.2 to +0.8mm from VIIc) to investigate the impact of GABAergic disinhibition on respiration. These injections consistently elicited ABD recruitment, but the response strength varied along the rostro-caudal zone. Remarkably, the most robust and enduring changes in tidal volume, minute ventilation and combined respiratory responses occurred at more rostral pFL locations (+0.6/+0.8 mm from VIIc). Multivariate analysis of the respiratory cycle further differentiated between locations, revealing the core site for active expiration generation with this experimental approach. Our study advances our understanding of neural mechanisms governing active expiration and emphasizes the significance of investigating the rostral pFL region.
Associations of onset age of breast cancer with incident myocardial infarction and heart failure: a prospective cohort study
Authors: Liang Jie , Pan Yang , Zhang Wenya , Gao Darui , Wang Yongqian , Xie Wuxiang , Zheng Fanfan
Published: June 2024

The associations of age at breast cancer onset with incident myocardial infarction (MI) and heart failure (HF) remain unexamined. Addressing this problem could promote understanding of the cardiovascular impact of breast cancer.Data were from the UK Biobank. Information on diagnosis of breast cancer, MI and HF were collected at baseline and follow-ups (median=12.8 years). Propensity score matching method and Cox proportional hazards models were employed.A total of 251,277 female participants (mean age: 56.8±8.0 years), of whom 16,241 had breast cancer, were included. Among participants with breast cancer, younger onset age (per 10-year decrease) was significantly associated with elevated risks of MI (HR=1.36, 95%CI: 1.19 to 1.56,
P
<0.001) and HF (HR=1.31, 95% CI: 1.18 to 1.46,
P
<0.001). After propensity score matching, breast cancer patients with younger onset age had significantly higher risks of MI and HF than healthy controls.Younger onset age of breast cancer was associated with higher risks of incident MI and HF, underscoring the necessity to pay additional attention to the cardiovascular health of breast cancer patients diagnosed at younger age to conduct timely intervention to attenuate the subsequent risks of incident cardiovascular diseases.
The mechanism of mammalian proton-coupled peptide transporters
Authors: Lichtinger Simon M , Parker Joanne L , Newstead Simon , Biggin Philip C
Published: June 2024

Proton-coupled oligopeptide transporters (POTs) are of great pharmaceutical interest owing to their promiscuous substrate binding site that has been linked to improved oral bioavailability of several classes of drugs. Members of the POT family are conserved across all phylogenetic kingdoms and function by coupling peptide uptake to the proton electrochemical gradient. Cryo-EM structures and alphafold models have recently provided new insights into different conformational states of two mammalian POTs, SLC15A1 and SLC15A2. Nevertheless, these studies leave open important questions regarding the mechanism of proton and substrate coupling, while simultaneously providing a unique opportunity to investigate these processes using molecular dynamics (MD) simulations. Here, we employ extensive unbiased and enhanced-sampling MD to map out the full SLC15A2 conformational cycle and its thermodynamic driving forces. By computing conformational free energy landscapes in different protonation states and in the absence or presence of peptide substrate, we identify a likely sequence of intermediate protonation steps that drive inward-directed alternating access. These simulations identify key differences in the extracellular gate between mammalian and bacterial POTs, which we validate experimentally in cell-based transport assays. Our results from constant-PH MD and absolute binding free energy (ABFE) calculations also establish a mechanistic link between proton binding and peptide recognition, revealing key details underpining secondary active transport in POTs. This study provides a vital step forward in understanding proton-coupled peptide and drug transport in mammals and pave the way to integrate knowledge of solute carrier structural biology with enhanced drug design to target tissue and organ bioavailability.
Role of hepatocyte RIPK1 in maintaining liver homeostasis during metabolic challenges
Authors: Zhang Weigao , Liu Hu , Zhang Danyang , Yi Yuguo , Tao Liang , Zhu Yunfeng , Huang Shuxian , Zhao Xunan , Shao Qianchao , Li Peiqi , Weng Yiwen , Lu Wei , Zhang Jianfa , Zhang Haibing , Chen Yuxin , Weng Dan
Published: June 2024

As a central hub for metabolism, the liver exhibits strong adaptability to maintain homeostasis in response to food fluctuations throughout evolution. However, the mechanisms governing this resilience remain incompletely understood. In this study, we identified Receptor interacting protein kinase 1 (RIPK1) in hepatocytes as a critical regulator in preserving hepatic homeostasis during metabolic challenges, such as short-term fasting or high-fat dieting. Our results demonstrated that hepatocyte-specific deficiency of RIPK1 sensitized the liver to short-term fasting-induced liver injury and hepatocyte apoptosis in both male and female mice. Despite being a common physiological stressor that typically does not induce liver inflammation, short-term fasting triggered hepatic inflammation and compensatory proliferation in hepatocyte-specific RIPK1-deficient (Ripk1-hepKO) mice. Transcriptomic analysis revealed that short-term fasting oriented the hepatic microenvironment into an inflammatory state in Ripk1-hepKO mice, with up-regulated expression of inflammation and immune cell recruitment-associated genes. Single-cell RNA sequencing further confirmed the altered cellular composition in the liver of Ripk1-hepKO mice during fasting, highlighting the increased recruitment of macrophages to the liver. Mechanically, our results indicated that ER stress was involved in fasting-induced liver injury in Ripk1-hepKO mice. Overall, our findings revealed the role of RIPK1 in maintaining liver homeostasis during metabolic fluctuations and shed light on the intricate interplay between cell death, inflammation, and metabolism.
Role of Hepatocyte RIPK1 in Maintaining Liver Homeostasis during Metabolic Challenges
Authors: Zhang Weigao , Zhang Danyang , Yi Yuguo , Tao Liang , Zhao Xunan , Shao Qianchao , Li Peiqi , Zhang Jianfa , Zhang Haibing , Chen Yuxin , Weng Dan
Published: June 2024

As a central hub for metabolism, the liver exhibits strong adaptability to maintain homeostasis in response to food fluctuations throughout evolution. However, the mechanisms governing this resilience remain incompletely understood. Receptor interacting protein kinase 1 (RIPK1) plays a key role in regulating cell survival, cell death, and inflammation. Despite extensive research on its involvement in various pathological conditions, the physiological role of RIPK1 remains relatively unexplored. In this study, we identified RIPK1 in hepatocytes as a critical regulator in preserving hepatic homeostasis during metabolic challenges, such as short-term fasting or high-fat dieting. Our results demonstrated that hepatocyte-specific deficiency of RIPK1 sensitized the liver to short-term fasting-induced liver injury and hepatocyte apoptosis in both male and female mice. Despite being a common physiological stressor that typically does not induce liver inflammation, short-term fasting triggered hepatic inflammation and compensatory proliferation in hepatocyte-specific RIPK1-deficient (

Ripk1
Δhep

) mice. Transcriptomic analysis revealed that short-term fasting oriented the hepatic microenvironment into an inflammatory state in

Ripk1
Δhep

mice, with upregulated expression of inflammation and immune cell recruitment-associated genes. Single-cell RNA sequencing further confirmed the altered cellular composition in the liver of

Ripk1
Δhep

mice during fasting, highlighting the increased recruitment of macrophages to the liver. Mechanically, our results indicated that ER stress was involved in fasting-induced liver injury in

Ripk1
Δhep

mice. Overall, our findings revealed the role of RIPK1 in maintaining liver homeostasis during metabolic fluctuations and shed light on the intricate interplay between cell death, inflammation, and metabolism.
Enteric glia regulate Paneth cell secretion and intestinal microbial ecology
Authors: Prochera Aleksandra , Muppirala Anoohya N. , Kuziel Gavin A. , Soualhi Salima , Shepherd Amy , Sun Liang , Issac Biju , Rosenberg Harry J. , Karim Farah , Perez Kristina , Smith Kyle H. , Archibald Tonora H. , Rakoff-Nahoum Seth , Hagen Susan J. , Rao Meenakshi
Published: June 2024

Glial cells of the enteric nervous system (ENS) interact closely with the intestinal epithelium and secrete signals that influence epithelial cell proliferation and barrier formation
in vitro
. Whether these interactions are important
in vivo,
however, is unclear because previous studies reached conflicting conclusions [1]. To better define the roles of enteric glia in steady state regulation of the intestinal epithelium, we characterized the glia in closest proximity to epithelial cells and found that the majority express
PLP1
in both mice and humans. To test their functions using an unbiased approach, we genetically depleted PLP1
+
cells in mice and transcriptionally profiled the small and large intestines. Surprisingly, glial loss had minimal effects on transcriptional programs and the few identified changes varied along the gastrointestinal tract. In the ileum, where enteric glia had been considered most essential for epithelial integrity, glial depletion did not drastically alter epithelial gene expression but caused a modest enrichment in signatures of Paneth cells, a secretory cell type important for innate immunity. In the absence of PLP1
+
glia, Paneth cell number was intact, but a subset appeared abnormal with irregular and heterogenous cytoplasmic granules, suggesting a secretory deficit. Consistent with this possibility, ileal explants from glial-depleted mice secreted less functional lysozyme than controls with corresponding effects on fecal microbial composition. Collectively, these data suggest that enteric glia do not exert broad effects on the intestinal epithelium but have an essential role in regulating Paneth cell function and gut microbial ecology.
Neuropeptide Bursicon and its receptor-mediated the transition from summer-form to winter-form of Cacopsylla chinensis
Authors: Zhang Zhixian , Li Jianying , Wang Yilin , Li Zhen , Liu Xiaoxia , Zhang Songdou
Published: June 2024

Seasonal polyphenism enables organisms to adapt to environmental challenges by increasing phenotypic diversity. Cacopsylla chinensis exhibits remarkable seasonal polyphenism, specifically in the form of summer-form and winter-form, which have distinct morphological phenotypes. Previous research has shown that low temperature and the temperature receptor CcTRPM regulate the transition from summer-form to winter-form in C. chinensis by impacting cuticle content and thickness. However, the underling neuroendocrine regulatory mechanism remains largely unknown. Bursicon, also known as the tanning hormone, is responsible for the hardening and darkening of the insect cuticle. In this study, we report for the first time on the novel function of Bursicon and its receptor in the transition from summer-form to winter-form in C. chinensis. Firstly, we identified CcBurs-α and CcBurs-β as two typical subunits of Bursicon in C. chinensis, which were regulated by low temperature (10 °C) and CcTRPM. Subsequently, CcBurs-α and CcBurs-β formed a heterodimer that mediated the transition from summer-form to winter-form by influencing the cuticle chitin contents and cuticle thickness. Furthermore, we demonstrated that CcBurs-R acts as the Bursicon receptor and plays a critical role in the up-stream signaling of the chitin biosynthesis pathway, regulating the transition from summer-form to winter-form. Finally, we discovered that miR-6012 directly targets CcBurs-R, contributing to the regulation of Bursicon signaling in the seasonal polyphenism of C. chinensis. In summary, these findings reveal the novel function of the neuroendocrine regulatory mechanism underlying seasonal polyphenism and provide critical insights into the insect Bursicon and its receptor.
Sir2 and Fun30 regulate ribosomal DNA replication timing via MCM helicase positioning and nucleosome occupancy
Authors: Lichauco Carmina , Foss Eric J , Gatbonton-Schwager Tonibelle , Athow Nelson F , Lofts Brandon , Acob Robin , Taylor Erin , Marquez James J , Lao Uyen , Miles Shawna , Bedalov Antonio
Published: June 2024

The association between late replication timing and low transcription rates in eukaryotic heterochromatin is well known, yet the specific mechanisms underlying this link remain uncertain. In Saccharomyces cerevisiae, the histone deacetylase Sir2 is required for both transcriptional silencing and late replication at the repetitive ribosomal DNA (rDNA) arrays. We have previously reported that in the absence of SIR2, a de-repressed RNA PolII repositions MCM replicative helicases from their loading site at the ribosomal origin, where they abut well-positioned, high-occupancy nucleosomes, to an adjacent region with lower nucleosome occupancy. By developing a method that can distinguish activation of closely spaced MCM complexes, here we show that the displaced MCMs at rDNA origins have increased firing propensity compared to the nondisplaced MCMs. Furthermore, we found that both activation of the repositioned MCMs and low occupancy of the adjacent nucleosomes critically depend on the chromatin remodeling activity of FUN30. Our study elucidates the mechanism by which Sir2 delays replication timing, and it demonstrates, for the first time, that activation of a specific replication origin in vivo relies on the nucleosome context shaped by a single chromatin remodeler.
Sir2 and Fun30 regulate ribosomal DNA replication timing via Mcm helicase positioning and nucleosome occupancy
Authors: Lichauco Carmina , Foss Eric J. , Gatbonton-Schwager Tonibelle , Athow Nelson F. , Lofts Brandon R. , Acob Robin , Taylor Erin , Lao Uyen , Miles Shawna , Bedalov Antonio
Published: June 2024

The association between late replication timing and low transcription rates in eukaryotic heterochromatin is well-known, yet the specific mechanisms underlying this link remain uncertain. In
Saccharomyces cerevisiae
, the histone deacetylase Sir2 is required for both transcriptional silencing and late replication at the repetitive ribosomal DNA arrays (rDNA). We have previously reported that in the absence of
SIR2
, a derepressed RNA PolII repositions MCM replicative helicases from their loading site at the ribosomal origin, where they abut well-positioned, high-occupancy nucleosomes, to an adjacent region with lower nucleosome occupancy. By developing a method that can distinguish activation of closely spaced MCM complexes, here we show that the displaced MCMs at rDNA origins have increased firing propensity compared to the non-displaced MCMs. Furthermore, we found that both, activation of the repositioned MCMs and low occupancy of the adjacent nucleosomes critically depend on the chromatin remodeling activity of
FUN30
. Our study elucidates the mechanism by which Sir2 delays replication timing, and it demonstrates, for the first time, that activation of a specific replication origin
in vivo
relies on the nucleosome context shaped by a single chromatin remodeler.
Mechano-regulation of GLP-1 production by Piezo1 in intestinal L cells
Authors: Huang Yanling , Mo Haocong , Yang Jie , Gao Luyang , Tao Tian , Shu Qing , Guo Wenying , Zhao Yawen , Lyu Jingya , Wang Qimeng , Guo Jinghui , Zhai Hening , Zhu Linyan , Chen Hui , Xu Geyang
Published: June 2024

Glucagon-like peptide 1 (GLP-1) is a gut-derived hormone secreted by intestinal L cells and vital for postprandial glycemic control. As open-type enteroendocrine cells, whether L cells can sense mechanical stimuli caused by chyme and thus regulate GLP-1 synthesis and secretion is unexplored. Our study showed expression of Piezo1 in intestinal L cells. Its level varied in different energy status and correlates with blood glucose and GLP-1 levels. Mice with L cell-specific loss of Piezo1 (

IntL-Piezo1
-/-

) exhibited impaired glucose tolerance, increased body weight, reduced GLP-1 production and decreased CaMKKβ/CaMKIV-mTORC1 signaling pathway under normal chow diet or high fed diet. Activation of the intestinal Piezo1 by its agonist Yoda1 or intestinal bead implantation increased the synthesis and secretion of GLP-1, thus alleviated glucose intolerance in diet-induced-diabetic mice. Overexpression of Piezo1, Yoda1 treatment or stretching stimulated GLP-1 production and CaMKKβ/CaMKIV-mTORC1 signaling pathway, which could be abolished by knockdown or blockage of Piezo1 in primary cultured mouse L cells and STC-1 cells. These findings suggest a previously undiscovered mechano-regulation of GLP-1 production in L cells, which may shed new light on the treatments of diabetes.
An adaptable, reusable, and light implant for chronic Neuropixels probes
Authors: Bimbard C. , Takács F. , Catarino J. A. , Fabre J. M. J. , Gupta S. , Lenzi S. C. , Melin M. D. , O’Neill N. , Orsolic I. , Robacha M. , Street J. S. , Teixeira J. , Townsend S. , van Beest E. H. , Zhang A. M. , Churchland A. K. , Duan C. A. , Harris K. D. , Kullmann D. M. , Lignani G. , Mainen Z. F. , Margrie T. W. , Rochefort N.L. , Wikenheiser A. M. , Carandini M. , Coen P.
Published: June 2024

Electrophysiology has proven invaluable to record neural activity, and the development of Neuropixels probes dramatically increased the number of recorded neurons. These probes are often implanted acutely, but acute recordings cannot be performed in freely moving animals and the recorded neurons cannot be tracked across days. To study key behaviors such as navigation, learning, and memory formation, the probes must be implanted chronically. An ideal chronic implant should (1) allow stable recordings of neurons for weeks; (2) allow reuse of the probes after explantation; (3) be light enough for use in mice. Here, we present the “Apollo Implant”, an open-source and editable device that meets these criteria and accommodates up to two Neuropixels 1.0 or 2.0 probes. The implant comprises a “payload” module which is attached to the probe and is recoverable, and a “docking” module which is cemented to the skull. The design is adjustable, making it easy to change the distance between probes, the angle of insertion, and the depth of insertion. We tested the implant across eight labs in head-fixed mice, freely moving mice, and freely moving rats. The number of neurons recorded across days was stable, even after repeated implantations of the same probe. The Apollo implant provides an inexpensive, lightweight, and flexible solution for reusable chronic Neuropixels recordings.