Major Research Advances Research Articles

Local and Noninvasive Glyco-Virus Checkpoint Nanoblockades Restrict Sialylation for Prolonged Broad-Spectrum Epidemic Virus Therapy.

The coronavirus disease 2019 (COVID-19) pandemic has driven major advances in virus research. The role of glycans in viral infection has been revealed, with research demonstrating that terminal sialic acids are key receptors during viral attachment and infection into host cells. However, there is an urgent demand for universal tools to study the mechanism of sialic acids in viral infections, as well as to develop therapeutic agents against epidemic viruses through the downregulation of terminal sialic acid residues on glycans acting as a glyco-virus checkpoint to accelerate virus clearance. In this study, we developed a robust sialic acids blockade tool termed local and noninvasive glyco-virus checkpoint nanoblockades (LONG NBs), which blocked cell surface sialic acids by endogenously and continuously inhibiting the de novo sialic acids biosynthesis pathway. Furthermore, LONG NBs could accurately characterize the sialic acid-dependent profiles of multiple virus variants and protected the host against partial SARS-CoV-2, rotavirus, and influenza A virus infections after local and noninvasive administration. Our results suggest that LONG NBs represent a promising tool to facilitate in-depth research on the mechanism of viral infection, and serve as a broad-spectrum protectant against existing and emerging viral variants via glyco-virus checkpoint blockade.

The beneficial health effects of puerarin in the treatment of cardiovascular diseases: from mechanisms to therapeutics.

Cardiovascular diseases (CVDs) are the leading causes of death globally that seriously threaten human health. Although novel western medicines have continued to be discovered over the past few decades to inhibit the progression of CVDs, new drug research and development for treating CVDs with less side effects and adverse reactions are continuously being desired. Puerarin is a natural product found in a variety of medicinal plants belonging to the flavonoid family with potent biological and pharmacological activities. Abundant research findings in the literature have suggested that puerarin possesses a promising prospect in treating CVDs. In recent years, numerous new molecular mechanisms of puerarin have been explored in experimental and clinical studies, providing new evidence for this plant metabolite to protect against CVDs. This article systematically introduces the history of use, bioavailability, and various dosage forms of puerarin and further summarizes recently published data on the major research advances and their underlying therapeutic mechanisms in treating CVDs. It may provide references for researchers in the fields of pharmacology, natural products, and internal medicine.

Neutrophil and neutrophil extracellular trap involvement in neutrophilic asthma: A review.

Asthma is a highly prevalent chronic inflammatory disease characterized by variable airflow obstruction and airway hyperresponsiveness. Neutrophilic asthma (NA) is classified as "type 2 low" asthma, defined as 65% or more neutrophils in the total cell count. There is no clear consensus on the pathogenesis of NA, and the accumulation of neutrophils and release of neutrophil extracellular traps (NETs) may be responsible for its development. A NET is a large extracellular meshwork comprising cell membrane and granule proteins. It is a powerful antimicrobial defence system that traps, neutralizes, and kills bacteria, fungi, viruses, and parasites and prevents the spread of microorganisms. However, dysregulation of NETs may lead to chronic airway inflammation, is associated with worsening of asthma, and has been the subject of major research advances in chronic lung diseases in recent years. NA is insensitive to steroids, and there is a need to find effective biomarkers as targets for the treatment of NA to replace steroids. This review analyses the mechanisms of action between asthmatic neutrophil recruitment and NET formation and their impact on NA development. It also discusses their possible therapeutic significance in NA, summarizing the advances made in NA agents and providing strategies for the treatment of NA, provide a theoretical basis for the development of new therapeutic drugs, thereby improving the level of diagnosis and treatment, and promoting the research progress in the field of asthma.

Development of orphan drugs for rare diseases.

Most rare diseases (orphan diseases) still lack approved treatment options despite major advances in research providing the necessary tools to understand their molecular basis and legislation providing regulatory and economic incentives to expedite the development of specific therapies. Addressing this translational gap is a multifaceted challenge, a key aspect of which is the selection of an optimal therapeutic modality to translate advances in rare disease knowledge to potential medicines known as orphan drugs. There are several strategies for developing orphan drugs for rare genetic disorders, including protein replacement therapies, small-molecule therapies (e.g., substrate reduction, chemical chaperone, cofactor, expression modification, and read-through therapies), monoclonal antibodies, antisense oligonucleotides, small interfering RNA or exon skipping therapies, gene replacement and direct genome-editing therapies, mRNA therapy, cell therapy, and drug repurposing. Each strategy has its own strengths and limitations in orphan drug development. Furthermore, numerous hurdles are present in clinical trials of rare genetic diseases because of difficulty with patient recruitment, unknown molecular physiology, the natural history of the disease, ethical concerns regarding pediatric patients, and regulatory challenges. To address these barriers, the rare genetic diseases community, including academic institutions, industry, patient advocacy groups, foundations, payers, and government regulatory and research organizations, must become engaged in discussions about these issues.

Sex-specific considerations in cardiovascular drug therapy.

Despite major advances in cardiac research over the past three decades, cardiovascular disease (CVD) still remains the leading cause of morbidity and mortality in women and men worldwide. However, a major challenge for health care providers is that the current guidelines for cardiovascular drug therapies do not consider the impact of sex in the development of treatment plan for optimizing therapies for women. Clinical research in recent years suggests significant pharmacological and pharmacokinetic differences between females and males, which have been attributed in part to differences in body composition, plasma protein binding capacity, drug metabolism, and excretion. Herein, we provide a comprehensive review regarding sex-specific differences and drugs commonly used for CVDs in women and men. Understanding how sex-related differences influence drug efficacy and CVD outcomes is crucial for not only optimizing treatment strategies for women and men but also to encourage the implementation of specific guidelines that address sex difference as a consideration for the treatment of CVDs.

Advancements in Image-Based Models for High-Grade Gliomas Might Be Accelerated.

The first half of 2022 saw the publication of several major research advances in image-based models and artificial intelligence applications to optimize treatment strategies for high-grade gliomas, the deadliest brain tumors. We review them and discuss the barriers that delay their entry into clinical practice; particularly, the small sample size and the heterogeneity of the study designs and methodologies used. We will also write about the poor and late palliation that patients suffering from high-grade glioma can count on at the end of life, as well as the current legislative instruments, with particular reference to Italy. We suggest measures to accelerate the gradual progress in image-based models and end of life care for patients with high-grade glioma.

Energy metabolism disturbance, altered neuronal development and glutamatergic signalling in human derived neuronal cell models of ADHD

Abstract Despite major advances in research into the neurobiological basis of mental illness, there have been hardly any new developments in new drug therapies. As there are approximately 30% of affected individuals that do not respond sufficiently to available treatments, there is a significant unmet medical need for new therapeutic approaches. About 90% of novel substances that have shown promise in animal studies are not effective in clinical trials. Recent research on human induced pluripotent stem cells (hiPSC) could lead to the use of more human-tailored models in this field. IPSC-derived cell models and organoids may be very attractive for preclinical screening and bridge the gap between in vitro and in vivo studies, reducing animal testing. However, the next steps must first demonstrate the validity and reproducibility of the initial functional results from the hIPSC models of mental illness. In our own studies on neuronal cell models of patients with attention-deficit/hyperactivity disorder (ADHD) with rare PARK2 gene variants, we were able to show evidence of mitochondrial dysfunction and impaired energy metabolism. Additionally, we have first hints at a oxidative dysbalance which could be as well targeted by medication. In a model of cortical development of ADHD patients with common variants in the ADGRL3 gene, we found first evidence for altered neuronal maturation as well as abnormalities in calcium metabolism and glutamatergic functionality compared to cells from healthy controls. In summary, these first results are promising that hIPSC models can contribute new insights into cellular pathomechanisms of mental and neurodevelopmental disorders and the development of new, individualised therapeutic approaches.Disclosure of InterestS. Kittel-Schneider Grant / Research support from: The studies are funded by IZKF Wuerzburg and BBRF fund (to SKS and RMcN). SKS received speaker’s honoraria from Takeda, Medice and Janssen.

Major clinical research advances in gynecologic cancer in 2023: a tumultuous year for endometrial cancer.

In the 2023 series, we summarized the major clinical research advances in gynecologic oncology based on communications at the conference of Asian Society of Gynecologic Oncology Review Course. The review consisted of 1) Endometrial cancer: immune checkpoint inhibitor, antibody drug conjugates (ADCs), selective inhibitor of nuclear export, CDK4/6 inhibitors WEE1 inhibitor, poly (ADP-ribose) polymerase (PARP) inhibitors. 2) Cervical cancer: surgery in low-risk early-stage cervical cancer, therapy for locally advanced stage and advanced, metastatic, or recurrent setting; and 3) Ovarian cancer: immunotherapy, triplet therapies using immune checkpoint inhibitors along with antiangiogenic agents and PARP inhibitors, and ADCs. In 2023, the field of endometrial cancer treatment witnessed a landmark year, marked by several practice-changing outcomes with immune checkpoint inhibitors and the reliable efficacy of PARP inhibitors and ADCs.

Cholesterol trafficking, lysosomal function, and atherosclerosis.

Despite years of study and major research advances over the past 50 years, atherosclerotic diseases continue to rank as the leading global cause of death. Accumulation of cholesterol within the vascular wall remains the main problem and represents one of the early steps in the development of atherosclerotic lesions. There is a complex relationship between vesicular cholesterol transport and atherosclerosis, and abnormalities in cholesterol trafficking can contribute to the development and progression of the lesions. The dysregulation of vesicular cholesterol transport and lysosomal function fosters the buildup of cholesterol within various intracytoplasmic compartments, including lysosomes and lipid droplets. This, in turn, promotes the hallmark formation of foam cells, a defining feature of early atherosclerosis. Multiple cellular processes, encompassing endocytosis, exocytosis, intracellular trafficking, and autophagy, play crucial roles in influencing foam cell formation and atherosclerotic plaque stability. In this review, we highlight recent advances in the understanding of the intricate mechanisms of vesicular cholesterol transport and its relationship with atherosclerosis and discuss the importance of understanding these mechanisms in developing strategies to prevent or treat this prevalent cardiovascular disease.

Intermittent Hypobaric Hypoxia Ameliorates Autistic-Like Phenotypes in Mice.

Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by persistent deficits in social communication and stereotyped behaviors. Although major advances in basic research on autism have been achieved in the past decade, and behavioral interventions can mitigate the difficulties that individuals with autism experience, little is known about the many fundamental issues of the interventions, and no specific medication has demonstrated efficiency for the core symptoms of ASD. Intermittent hypobaric hypoxia (IHH) is characterized by repeated exposure to lowered atmospheric pressure and oxygen levels, which triggers multiple physiological adaptations in the body. Here, using two mouse models of ASD, male Shank3B -/- and Fmr1 -/y mice, we found that IHH training at an altitude of 5,000 m for 4 h per day, for 14 consecutive days, ameliorated autistic-like behaviors. Moreover, IHH training enhanced hypoxia inducible factor (HIF) 1α in the dorsal raphe nucleus (DRN) and activated the DRN serotonergic neurons. Infusion of cobalt chloride into the DRN, to mimic IHH in increasing HIF1α expression or genetically knockdown PHD2 to upregulate HIF1α expression in the DRN serotonergic neurons, alleviated autistic-like behaviors in Shank3B -/- mice. In contrast, downregulation of HIF1α in DRN serotonergic neurons induced compulsive behaviors. Furthermore, upregulating HIF1α in DRN serotonergic neurons increased the firing rates of these neurons, whereas downregulation of HIF1α in DRN serotonergic neurons decreased their firing rates. These findings suggest that IHH activated DRN serotonergic neurons via upregulation of HIF1α, and thus ameliorated autistic-like phenotypes, providing a novel therapeutic option for ASD.

Major advances in epilepsy research in 2023

Major advances in epilepsy research in 2023

Who Is Curating My Political Feed? Characterizing Political Exposure of Registered U.S. Voters on Twitter

Social media platforms offer people a variety of options to engage with politics, from directly following elected officials to discussing politics with social peers. Despite major advances in recent research on online political exposure through the lens of selective exposure, filter bubbles, and ideological echo chambers, little is known about the fundamental questions of what types of political actors people are exposed to on social media, and how these distinctive types vary across sociodemographic groups. We address this gap in the literature by analyzing unique panel data on more than 600,000 registered U.S. voters on Twitter during the 2020 U.S. Presidential campaign. We analyze this dataset to identify distinct types of political consumers and how they vary in terms of sociodemographics. Our findings suggest that the bulk of the population has a meaningful share of political content available from social peers, that the majority of this content originates from traditional sources of political information (media organizations, journalists, and politicians), and that media organizations are the dominant and direct source of political information on Twitter for nearly 20% of the sample population. These results advance our understanding of the way citizens learn about politics in new media and pave the way for next-step research to identify the causal effect of exposure to distinct curators of political content on individuals’ political attitudes and political behavior.

Transcription factor E4F1 as a regulator of cell life and disease progression.

E4F transcription factor 1 (E4F1), a member of the GLI-Kruppel family of zinc finger proteins, is now widely recognized as a transcription factor. It plays a critical role in regulating various cell processes, including cell growth, proliferation, differentiation, apoptosis and necrosis, DNA damage response, and cell metabolism. These processes involve intricate molecular regulatory networks, making E4F1 an important mediator in cell biology. Moreover, E4F1 has also been implicated in the pathogenesis of a range of human diseases. In this review, we provide an overview of the major advances in E4F1 research, from its first report to the present, including studies on its protein domains, molecular mechanisms of transcriptional regulation and biological functions, and implications for human diseases. We also address unresolved questions and potential research directions in this field. This review provides insights into the essential roles of E4F1 in human health and disease and may pave the way for facilitating E4F1 from basic research to clinical applications.

"Hurdles race for CAR T-cell therapy in digestive tract cancer".

Digestive tract cancers (DTC) belong to the most investigated family of tumors. The incidence, prevalence, and mortality rate of DTC remain high, especially for patients with pancreatic cancer. Even though immunotherapy such as immune checkpoint inhibitors (ICI) have revolutionized the treatment of solid cancer types, ICI are still restricted to a very small group of patients and seem to be more efficacious in combination with chemotherapy. Cellular immunotherapy such as CAR T-cell therapy has entered clinical routine in hematological malignancies with outstanding results. There is growing interest on translating this kind of immunotherapy and success into patients with solid malignancies, such as DTC. This review attempts to describe the major advances in preclinical and clinical research with CAR T cells in DTC, considering the most relevant hurdles in each subtype of DTC.

Advancement and Applications of Nanotherapy for Cancer Immune Microenvironment.

Cancer treatment has evolved rapidly due to major advances in tumor immunity research. However, due to the complexity, heterogeneity, and immunosuppressive microenvironment of tumors, the overall efficacy of immunotherapy is only 20%. In recent years, nanoparticles have attracted more attention in the field of cancer immunotherapy because of their remarkable advantages in biocompatibility, precise targeting, and controlled drug delivery. However, the clinical application of nanomedicine also faces many problems concerning biological safety, and the synergistic mechanism of nano-drugs with immunity remains to be elucidated. Our study summarizes the functional characteristics and regulatory mechanisms of nanoparticles in the cancer immune microenvironment and how nanoparticles activate and long-term stimulate innate immunity and adaptive immunity. Finally, the current problems and future development trends regarding the application of nanoparticles are fully discussed and prospected to promote the transformation and application of nanomedicine used in cancer treatment.

『조직과 인사관리연구』 45주년

This article reviews major advances in research on organizational behavior(OB) published in Journal of Organization and Management from 2009 to 2022 to commemorate the 45th anniversary of the founding of the Korean Academy of Organization and Management. Specifically based on the article analysis criteria used by Park & Kim (2010), the research topic and methodology of the published articles in the field of OB were analyzed. Moreover, this article examines the contribution of Journal of Organization and Management to the theoretical field by analyzing the micro-organization theories used in published articles. The analysis results of 220 of the 349 articles in the field of OB, including research methodology, revealed that the research topics were diversified compared with those in the early 30 years since the founding of Journal of Organizational and Management. However, in terms of the research methodology, we identified that it was mostly quantitative and hypothesis testing in nature. The micro-organizational theory analysis revealed that 78 theories, grouped into 13 theoretical categories, were used in the articles published in the area of OB, Social exchange theory and conservation of resource theory were the most frequently used theories. Based on these findings, we recommend that various articles with the potential for theoretical contribution in the two dimensions- namely, theory building and testing-be encouraged for publication in Journal of Organization and Management. We also suggest that there should be linkages between the research and practical area so that researchers can be motivated by actual data from the organization. Lastly, We conclude with a discussion of building the journal’s culture and identity to embrace domestic OB researchers.

Pisum Sustainability System to Na2SO4

Salinity is a major abiotic stress limiting growth and productivity of plants in many areas of the world due to increasing use of poor quality of water for irrigation and soil salinization. Plant adaptation or sustainability to salinity stress involves complex physiological traits, metabolic pathways, and molecular or gene networks. A comprehensive understanding on how plants respond to salinity stress at different levels and an integrated approach of combining molecular tools with physiological and biochemical techniques are imperative for the development of salt-stable varieties of plants in salt-affected areas. Recent research has identified various adaptive responses to salinity stress at molecular, cellular, metabolic, and physiological levels, although mechanisms underlying salinity tolerance are far from being completely understood. This paper provides a comprehensive review of major research advances on biochemical, physiological, and molecular mechanisms regulating plant adaptation and sustainability to salinity stress.

TREX1 cytosolic DNA degradation correlates with autoimmune disease and cancer immunity.

Three Prime Repair Exonuclease 1 (TREX1) is a major 3'-5' exonuclease in mammalian cells that primarily degrades DNA substrates in the cytoplasm. TREX1 deficiency results in an aberrant accumulation of self-DNA in the cytosol, predominantly activating the innate immune response via the cGAS-STING-IFN pathways. Characterized by interferon production, autoimmune diseases, such as Aicardi-Goutieres syndrome (AGS), systemic lupus erythematosus (SLE), familial chilblain lupus (FCL), and retinal vasculopathy and leukodystrophy (RVCL), are associated with TREX1 loss of function. Besides, abnormal expression of TREX1 also appears in different types of tumor cells. In this review, we described the structure and mechanisms of TREX1 in degrading self-DNA and discussed the potential sources of these aberrant nucleic acids. We also summarized the major research advances in TREX1-related diseases, including autoimmune diseases and cancer. These contents will serve as a foundation for further study on the function of TREX1 and provide advances in the diagnosis, treatment, and prognosis of related disorders.

Coregistered transcranial optoacoustic and magnetic resonance angiography of the human brain.

Imaging modalities capable of visualizing the human brain have led to major advances in neurology and brain research. Multi-spectral optoacoustic tomography (MSOT) has gained importance for studying cerebral function in rodent models due to its unique capability to map changes in multiple hemodynamic parameters and to directly visualize neural activity within the brain. The technique further provides molecular imaging capabilities that can facilitate early disease diagnosis and treatment monitoring. However, transcranial imaging of the human brain is hampered by acoustic attenuation and other distortions introduced by the skull. Here, we demonstrate non-invasive transcranial MSOT angiography of pial veins through the temporal bone of an adult healthy volunteer. Time-of-flight (TOF) magnetic resonance angiography (MRA) and T1-weighted structural magnetic resonance imaging (MRI) were further acquired to facilitate anatomical registration and interpretation. The superior middle cerebral vein in the temporal cortex was identified in the MSOT images, matching its location observed in the TOF-MRA images. These initial results pave the way toward the application of MSOT in clinical brain imaging.

Knowledge extraction and performance improvement of Bi2Te3-based thermoelectric materials by machine learning

Major advances in materials research often require serendipity and chemical intuition. Traditional trial-and-error-based experimental studies are becoming insufficient for designing novel high-performance materials because of staggering degree of freedom in materials' processing and composition. This work employed machine learning to aid the design of hot-extruded Bi2Te2.85Se0.15 bulk thermoelectric materials based on a small amount of in-house experimental data. Surprisingly, it was found that a combination of processing/composition design strategy with higher extrusion temperatures, more Cu dopants, and deficiency of Te, which is contradictory to experimental experiences, could enhance the materials’ figure of merit (ZT). Experimental validation demonstrated that such a processing/composition solution effectively suppressed formation of point defects, refined microstructure, and promoted evolution of a “fiber texture”, thus simultaneously improving thermoelectric and mechanical properties. The data-driven strategy breaks the rules of thumb in traditional experimental studies and extracts new knowledge to guide the design of high-performance Bi2Te3-based bulk thermoelectric materials.