Important Functions Research Articles

The Impact of Your Leadership in Human Resource Management: An Exploratory Study on the Oil Marketing Company

The importance of the marketing function at board level is often underestimated and its role in driving change in HR is often undervalued. This research examines how marketing can partner with organizational leadership for a mutually beneficial exchange of marketing skills and capabilities to be able to realign human resources quickly enough to deal with shifts in the external business environment and create a sustainable future for the business. The current research explores the concept of “marketing leadership” from an interpretive perspective that challenges the traditional view of marketing and leadership as two separate domains and offers a comprehensive approach to human resource management. The descriptive survey method was used for this research, and the research population was the oil marketing company. The current research assumed that marketing leadership affects human resources management. The research concluded that marketing leadership greatly affects human resources management and its dimensions, with an average effect of (0.52). This indicates a high and significant impact of marketing leadership on human resources management.

8464 A Unique SERM Reveals An Estrogen Receptor-Dependent Secretion Of DKK1 In Breast Cancer Cells

Abstract Disclosure: K.S. Young: None. G. Hancock: None. S. Kregel: None. S.W. Fanning: Grant Recipient; Self; Olema Oncology. Although Estrogen Receptor positive (ER+) breast cancer has been successfully targeted in primary tumors, the critical limitations of hormone therapies are ultimately revealed as many women often experience disease recurrence. A subset of these patients harbor a distinctive tyrosine to serine missense mutation at position 537 (Y537S) in ER leading to allele-specific transcriptional programs that enhance metastasis. ER is a ligand-dependent master transcriptional regulator. Probing unique ER structural features can reveal new transcriptional activities. We developed a structurally unconventional Selective Estrogen Receptor Modulator (SERM), T6I-29, to better understand these structure-transcriptional relationships. T6I-29 shows effective anti-tumoral activities in Y537S ESR1 breast cancer cells. To examine the anti-tumoral mechanism of T6I-29 action, we performed RNA-sequencing on ESR1 Y537S mutant breast cancer cells. Compared to other clinically relevant compounds, our drug uniquely and significantly downregulated DKK1, a tumor secreted protein known to modulate the Wnt/β-Catenin and PI3K/Akt pathways. Upregulation of DKK1 correlates with metastatic burden across multiple cancers but has not been evaluated in ESR1 mutant breast cancers. We find that DKK1 levels are significantly elevated in the plasma of 108 ER+ breast cancer patients compared to 100 matched healthy donors. Furthermore, in wild-type (WT) PIK3CA breast cancer cell lines, those with Y537S ESR1 mutation show constitutive expression and secretion of DKK1, while DKK1 expression and secretion is estrogen-dependent in WT breast cancer cells. Intriguingly, WT cells show significant surface bound DKK1, which is secreted into the media upon hormone stimulation and blocked by T6I-29. Understanding the ER-dependence and functional importance of DKK1 secretion offers a novel approach to potentially reduce breast cancer metastatic burden. Presentation: 6/3/2024

Evolution of the conformational dynamics of the molecular chaperone Hsp90

Hsp90 is a molecular chaperone of central importance for protein homeostasis in the cytosol of eukaryotic cells, with key functional and structural traits conserved from yeast to man. During evolution, Hsp90 has gained additional functional importance, leading to an increased number of interacting co-chaperones and client proteins. Here, we show that the overall conformational transitions coupled to the ATPase cycle of Hsp90 are conserved from yeast to humans, but cycle timing as well as the dynamics are significantly altered. In contrast to yeast Hsp90, the human Hsp90 is characterized by broad ensembles of conformational states, irrespective of the absence or presence of ATP. The differences in the ATPase rate and conformational transitions between yeast and human Hsp90 are based on two residues in otherwise conserved structural elements that are involved in triggering structural changes in response to ATP binding. The exchange of these two mutations allows swapping of the ATPase rate and of the conformational transitions between human and yeast Hsp90. Our combined results show that Hsp90 evolved to a protein with increased conformational dynamics that populates ensembles of different states with strong preferences for the N-terminally open, client-accepting states.

Relevance of charged and polar amino acids for functionality of membrane toxin TisB

Bacterial dormancy is marked by reduced cellular activity and the suspension of growth. It represents a valuable strategy to survive stressful conditions, as exemplified by the long-term tolerance towards antibiotics that is attributable to a fraction of dormant cells, so-called persisters. Here, we investigate the membrane toxin TisB (29 amino acids) from the chromosomal toxin-antitoxin system tisB/istR-1 in Escherichia coli. TisB depolarizes the inner membrane in response to DNA damage, which eventually promotes a stress-tolerant state of dormancy within a small fraction of the population. Using a plasmid-based system for moderate tisB expression and single amino acid substitutions, we dissect the importance of charged and polar amino acids. We observe that the central amino acids lysine 12 and glutamine 19 are of major importance for TisB functionality, which is further validated for lysine 12 in the native context upon treatment with the DNA-damaging antibiotic ciprofloxacin. Finally, we apply a library-based approach to test additional TisB variants in higher throughput, revealing that at least one positive charge at the C-terminus (either lysine 26 or 29) is mandatory for TisB-mediated dormancy. Our study provides insights into the molecular basis for TisB functionality and extends our understanding of bacterial membrane toxins.

Kaplan fibers of iliotibial band: a comprehensive review of current literature.

This review highlights the pivotal role of Kaplan fibers (KFs) in knee stability, particularly in the anterolateral aspect. Studies reveal their complex anatomy with varying attachments to the distal femur, demonstrating a significant impact on knee joint mechanics across different populations. Investigations into the biomechanics of KFs show their crucial role in maintaining rotational stability of the knee, especially during rotational movements. Their synergistic function with other knee structures, like the anterolateral ligament, is emphasized, underscoring their importance in knee integrity and function. MRI emerges as a key tool in detecting KFs, with varying visibility and prevalence of injuries. The review discusses the development of MRI criteria for accurate diagnosis, highlighting the need for further research to refine these criteria and understand the interplay between KF injuries, anterior cruciate ligament (ACL) ruptures, and associated knee pathologies. The review covers various lateral extra-articular tenodesis (LET) techniques used to address residual laxity and instability following ACL reconstruction. Among them, the modified Lemaire technique, which resembles the anatomical and functional characteristics of distal KFs, shows effectiveness in reducing internal rotation and residual laxity. The review emphasizes the need for further research to understand the healing dynamics of KF injuries and the efficacy of different LET techniques. It suggests that a comprehensive approach, considering both biomechanical and clinical aspects, is crucial for advancing knee joint health and rehabilitation.

Emerging roles of osteocytes in regulation of bone and skeletal muscle mass.

Contrary to the popular perception that the bone is merely a structural organ, decades of research have established its functional importance in whole-body metabolism. Osteocytes, which comprise >80% of all bone cells, were also initially thought to be terminally differentiated dormant cells lacking metabolic functions. However, new research is increasingly providing evidence that osteocytes not only play a role in the structural integrity of the bone, but also have secretory functions which regulate other bone cells as well as other organs including skeletal muscle - the structural-mechanical neighbor of the bone - via paracrine, and endocrine pathways. However, the publicly available preclinical and clinical data pertaining to the factors secreted by osteocytes and their functions in the musculoskeletal system largely fail to reach a consensus. This review is thus aimed to objectively collate all information available in the public domain for efficient access by researchers in the field. We strongly believe that this review will help researchers in an unbiased design of therapeutic strategies for musculoskeletal disorders.

Complete analysis of G-quadruplex forming sequences in the gapless assembly of human chromosome Y

Recent advancements have finally delivered a complete human genome assembly, including the elusive Y chromosome. This accomplishment closes a significant knowledge gap. Prior efforts were hampered by challenges in sequencing repetitive DNA structures such as direct and inverted repeats. We used the G4Hunter algorithm to analyze the presence of G-quadruplex forming sequences (G4s) within the current human reference genome (GRCh38) and the new telomere-to-telomere (T2T) Y chromosome assemblies. This analysis served a dual purpose: identifying the location of potential G4s within the genomes and exploring their association with functionally annotated sequences. Compared to GRCh38, the T2T assembly exhibited a significantly higher prevalence of G-quadruplex forming sequences. Notably, these repeats were abundantly located around precursor RNA, exons, genes, and within protein binding sites. This remarkable co-occurrence of G4-forming sequences with these critical regulatory regions suggests their role in fundamental DNA regulation processes. Our findings indicate that the current human reference genome significantly underestimated the number of G4s, potentially overlooking their functional importance.

Nebivolol-induced hepatoxicity: a case report

Nebivolol is a third-generation beta-blocker known for its high selectivity for beta-1 adrenergic receptors and its unique ability to induce vasodilation via nitric oxide (NO) release. Nebivolol, despite its favourable safety profile, can lead to significant liver injury. We describe the case of a 73-year-old hypertensive patient who developed significant liver enzyme elevations following the addition of nebivolol to her treatment regimen. Comprehensive workup ruled out other causes, leading to a diagnosis of drug-induced hepatotoxicity. Discontinuation of nebivolol resulted in normalization of liver enzymes. This case underscores the importance of monitoring liver function during beta-blocker therapy, particularly with nebivolol.

Morphofunctional assessment in patients with head and neck cancer. Importance of muscle mass and function

Morphofunctional assessment in patients with head and neck cancer. Importance of muscle mass and function

Mitochondrial DNA replication is essential for neurogenesis but not gliogenesis in fetal neural stem cells.

Mitochondria are unique organelles that have their own genome (mtDNA) and perform various pivotal functions within a cell. Recently, evidence has highlighted the role of mitochondria in the process of stem cell differentiation, including differentiation of neural stem cells (NSCs). Here we studied the importance of mtDNA function in the early differentiation process of NSCs in two cell culture models: the CGR8-NS cell line that was derived from embryonic stem cells by a lineage selection technique, and primary NSCs that were isolated from embryonic day 14 mouse fetal forebrain. We detected a dramatic increase in mtDNA content upon NSC differentiation to adapt their mtDNA levels to their differentiated state, which was not accompanied by changes in mitochondrial transcription factor A expression. As chemical mtDNA depletion by ethidium bromide failed to generate living ρ° cell lines from both NSC types, we used inhibition of mtDNA polymerase-γ by 2'-3'-dideoxycytidine to reduce mtDNA replication and subsequently cellular mtDNA content. Inhibition of mtDNA replication upon NSC differentiation reduced neurogenesis but not gliogenesis. The mtDNA depletion did not change energy production/consumption or cellular reactive oxygen species (ROS) content in the NSC model used. In conclusion, mtDNA replication is essential for neurogenesis but not gliogenesis in fetal NSCs through as yet unknown mechanisms, which, however, are largely independent of energy/ROS metabolism.

Comparative Analysis of Vitamin D, Folic Acid, and Trace Minerals Levels in Various Stages of Invasive Ductal Breast Cancer.

Invasive ductal carcinoma (IDC) is one of the most commonly diagnosed subtypes of breast cancer, representing the majority of breast cancer cases. This study investigates the levels of vitamin D, folic acid, and antioxidant minerals (zinc (Zn), copper (Cu), and magnesium (Mg)) in IDC patients across different disease stages to explore their potential roles in disease progression. We analyzed a cohort of 150 female patients with IDC, aged between 30 and 67 years (51 ± 15.5 years). Blood samples were collected to measure levels of vitamin D, folic acid, Cu, Mg, and Zn. Patients were categorized into Stage1 to Stage 4 of cancer. Variations in nutrient levels across these stages were statistically assessed using ANOVA and post-hoc tests. The study results revealed varying levels of key nutrients across different stages of the disease. Vitamin D levels averaged 17.7 ng/mL, with higher concentrations in early-stage patients, indicating a possible correlation with disease severity. Folic acid levels had a mean of 12.2 ng/mL, showing a decline in later stages, potentially linking it to cancer progression. Copper levels averaged 161.3μg/dL, peaking at 170μg/dL in Stage 3, suggesting a connection with cancer aggressiveness. Magnesium levels, with an average of 1.4 mg/dL, dropped notably to 0.6 mg/dL by Stage 4, highlighting its possible involvement in disease progression. Zinc levels averaged 69.4 μg/dL, with a significant decrease in advanced stages, emphasizing its importance for immune function and cellular health. The study demonstrates significant variations in the levels of vitamin D, folic acid, and antioxidant minerals across different stages of IDC. These nutrients may influence cancer progression, underscoring the potential benefits of nutritional assessments and interventions in managing IDC.

EnhancerNet: a predictive model of cell identity dynamics through enhancer selection.

Understanding how cell identity is encoded by the genome and acquired during differentiation is a central challenge in cell biology. I have developed a theoretical framework called EnhancerNet, which models the regulation of cell identity through the lens of transcription factor-enhancer interactions. I demonstrate that autoregulation in these interactions imposes a constraint on the model, resulting in simplified dynamics that can be parameterized from observed cell identities. Despite its simplicity, EnhancerNet recapitulates a broad range of experimental observations on cell identity dynamics, including enhancer selection, cell fate induction, hierarchical differentiation through multipotent progenitor states and direct reprogramming by transcription factor overexpression. The model makes specific quantitative predictions, reproducing known reprogramming recipes and the complex haematopoietic differentiation hierarchy without fitting unobserved parameters. EnhancerNet provides insights into how new cell types could evolve and highlights the functional importance of distal regulatory elements with dynamic chromatin in multicellular evolution.

Remodeling of T-Tubules and Associated Calcium Handling Dysfunction in Heart Failure: Mechanisms and Therapeutic Insights

In cardiomyocytes, transverse tubules (T-tubules) are sarcolemmal invaginations that facilitate excitation-contraction coupling (ECC) and diastolic function. The clinical significance of T-tubules has become evident as their remodeling is recognized as a hallmark feature of heart failure (HF) and a key contributor to disrupted Ca2+ homeostasis, compromised cardiac function, and arrhythmogenesis. Further investigations have revealed that T-tubule remodeling is particularly pronounced in HF with reduced ejection fraction (HFrEF), but not in HF with preserved ejection fraction (HFpEF), implying that T-tubule remodeling may play a crucial pathophysiological role in HFrEF. While research on the functional importance of T-tubules is ongoing due to their complexity, T-tubule remodeling has been found to be reversible. Such finding has triggered a surge in studies aimed at identifying specific therapeutic approaches for HFrEF. This review discusses the functional importance of T-tubules and their microdomains, the pathophysiology of T-tubule remodeling, and the potential mechanisms of current HFrEF therapeutic approaches in reversing T-tubule alterations. We also highlight discrepancies regarding the roles of T-tubule proteins in the recovery process across studies to offer valuable insights for future research.

Caspase-1-dependent spatiality in triple-negative breast cancer and response to immunotherapy.

Tumor immune microenvironment (TIME) spatial organization predicts outcome and therapy response in triple-negative breast cancer (TNBC). An immunosuppressive TIME containing elevated tumor-associated macrophages (TAM) and scarce CD8+ T cells is associated with poor outcome, but the regulatory mechanisms are poorly understood. Here we show that ETS1-driven caspase-1 expression, required for IL1β processing and TAM recruitment, is negatively regulated by estrogen receptors alpha (ERα) and a defining feature of TNBC. Elevated tumoral caspase-1 is associated with a distinct TIME characterized by increased pro-tumoral TAMs and CD8+ T cell exclusion from tumor nests. Mouse models prove the functional importance of ERα, ETS1, caspase-1 and IL1β in TIME conformation. Caspase-1 inhibition induces an immunoreactive TIME and reverses resistance to immune checkpoint blockade, identifying a therapeutically targetable mechanism that governs TNBC spatial organization.

Testing source elevation versus genotype as predictors of sugar pine performance in a post‐fire restoration planting

AbstractClimate change is motivating a reassessment of how seeds are selected for reforestation, as rapid environmental change can lead to local maladaptation in trees. Genetic association studies and past seed source climate both have the potential to help identify appropriate planting stock, but these techniques have not been compared and tested as part of an operational planting program. In this study, we combined an analysis of single nucleotide polymorphisms (SNPs) associated with environmental gradients in sugar pine (Pinus lambertiana) with an analysis of post‐fire seedling survival and growth in a restoration experiment. Our genotype–environment association (GEA) tests of 92 individuals from varying climates within CA revealed 829 SNPs (out of 300,604) with significant association with climate gradients, especially April snowpack. Of these, 323 either had annotations that suggested potential functional importance or were identified by two different methods. We then built Bayesian models of survival and growth for all seedlings in a separate post‐fire planting experiment, to test the relative predictive ability of source elevation (a common proxy for source climate) versus the proportion of seedling alleles expected to be locally advantageous based on GEA. Across three sites within the King Fire scar in Eldorado National Forest in 2017, 2018, and 2019, 1774 seedlings were planted. Of these, 206 had enough green needles in 2020 to allow sample collection, and 161 were successfully genotyped. We found that source elevation was generally better at predicting seedling performance than genotype indices, perhaps because of the limited scope of the association analysis. Seed sources from 500 to 1800 ft (152.4–548.6 m) lower in elevation, and one seed zone further south generally performed as well or better than local seed sources. This result, and those of similar previous studies, suggest that “climate matching” using past climate information for existing seed sourcing units is a reasonable starting point for finding seedlings suited to already‐altered planting site climate conditions. However, further tests with more extensive genomic and performance data may improve the utility of genotype information for seed selection.

Characterization of the Three DHFRs and K65P Variant: Enhanced Substrate Affinity and Molecular Dynamics Analysis.

Dihydrofolate reductase (DHFR) is ubiquitously present in all living organisms and plays a crucial role in the growth of the fungal pathogen R.solani. Sequence alignment confirmed the evolutionary conservation of the essential lid domain, with the amino acid 'P' within the PEKN lid domain appearing with a frequency of 89.5% in higher organisms and 11.8% in lower organisms. Consequently, a K65P variant was introduced into R.solani DHFR (rDHFR). Subsequent enzymatic kinetics assays were conducted for human DHFR (hDHFR), rDHFR, E. coli DHFR (eDHFR), and the K65P variant. hDHFR exhibited the highest kcat of 0.95s-1, followed by rDHFR with 0.14s-1, while eDHFR displayed the lowest kcat of 0.09s-1. Remarkably, the K65P variant induced a significant reduction in Km, resulting in a 1.8-fold enhancement in catalytic efficiency (kcat/Km) relative to the wild type. Differential scanning fluorimetry and binding free energy calculations confirmed the enhanced substrate affinity for both folate and NADPH in the K65P variant. These results suggest that the K65P mutation enhances substrate affinity and catalytic efficiency in DHFR, highlighting the evolutionary and functional importance of the K65 residue.

The Role of the Orbitofrontal Cortex in the Regulation of Fear Coping Strategies.

Under threats, individuals exhibit freezing behavior and prepare for active coping. The ability to flexibly shift between freezing and active coping increases survival chances in animals and decreases susceptibility to mental disorders among human beings. For example, patients with psychiatric disorders, such as obsessive-compulsive disorder and posttraumatic stress disorder, often show maladaptive coping behaviors. The orbitofrontal cortex (OFC) is a critical hub to process higher cognitive functions, sensory inputs, reward learning, and decision-making. It also regulates negative emotions and its aberrant activation level often correlates with numerous mental disorders. The rodent OFC comprises different subdivisions with varying connections to cortical and subcortical regions. Among these subdivisions, the medial orbital area (MO) and the lateral orbital area (LO) have distinct functions in the regulation of fear. Here, we updated the existing rodent literature studying the function of the OFC, with a particular focus on the MO and the LO in different coping strategies of animals. By examining the role of the OFC in the mediation of defensive coping strategies, we aim to deepen the understanding of its functional importance on mental health.

학령기 아동의 부모애착 및 부모의 민주적 양육행동과 초기 청소년기 학교적응 간의 관계에서 집행기능곤란의 매개효과

Objective: This study was conducted to verify the mediating effect of executive function difficulties in the relationship between school adaption in early adolescence and children’s parental attachment and democratic parenting behavior in school-age. Methods: Data of 9-year-olds from the 11th (2018) to 12-year-olds from the 14th (2021) Panel Study on Korean Children were used to extract variable data that fit the purpose of this study. Descriptive statistics were performed using SPSS 21.0, and AMOS 21.0 was used to analyze correlation, structural equation modeling, and mediating effects through bootstrapping to verify the research hypothesis model. Results: First, school-age children’s attachment to their parents had a direct positive effect on school adaptation in early adolescence, but parents’ democratic parenting behavior did not. Second, executive function fully mediated the relationship between democratic parenting behavior and school adaptation, and partially mediated the effect of parental attachment on school adaption. Conclusion: Executive function, secure parental attachment, and democratic parenting behavior in school-age children tended to reduce executive function difficulties in early adolescence. These results are discussed in terms of need to develop parent education programs to increase attachment to parents and teach desirable parenting behaviors. Also discussed to provide continuous and systematic guidance and education on the importance of executive function to parents.

NOD2-mediated dual negative regulation of inflammatory responses triggered by TLRs in the gastrointestinal tract.

Loss-of-function mutations in nucleotide-binding oligomerization domain 2 (NOD2) constitute the primary risk factors for Crohn's disease. NOD2 is an intracellular sensor for muramyl dipeptide (MDP), a small molecule derived from the peptidoglycan layer of bacterial cell wall. Although NOD2 is involved in host immune responses, much attention has been paid to the involvement of NOD2 in the maintenance of intestinal homeostasis. Despite the fact that the proinflammatory cytokine and chemokine responses induced by NOD2 activation alone are weaker than those induced by toll-like receptors (TLRs), NOD2 plays a crucial role in host defense against invading pathogens and in the regulation of immune responses. Recent studies have highlighted the importance of negative regulatory functions of NOD2 in TLRs-mediated proinflammatory cytokine responses. MDP-mediated activation of NOD2 induces interferon regulatory factor 4 (IRF4) expression, thereby suppressing nuclear factor-κB-dependent colitogenic cytokine responses through the inhibition of Lys(K)63-linked polyubiquitination on receptor-interacting serine/threonine protein kinase 2. MDP-mediated activation of NOD2 also downregulates TLR9-induced type I IFN responses by inhibiting the K63-linked polyubiquitination of TNF receptor-associated factor 3 via deubiquitinating enzyme A (DUBA) expression. Thus, NOD2 exerts dual negative regulation of TLRs-mediated proinflammatory cytokine and type I IFN responses by inducing the expression of IRF4 and DUBA, respectively. In this review, we summarize the molecular mechanisms whereby NOD2 activation suppresses TLRs-mediated proinflammatory and type I IFN responses. In addition, we discuss the clinical relevance of the NOD2-mediated negative regulation of TLRs in inflammatory bowel disease.

The distribution of seaweed forms and foundational assumptions in seaweed biology

Seaweeds are the most phylogenetically diverse group of multicellular organisms and rank foremost among marine keystone species. Due to their taxonomic diversity and functional importance, previous studies have classified seaweeds into functional groups based on qualitative or semi-quantitative traits, such as seaweed form, anatomy, and thickness. Despite the widespread use of seaweed functional groups from basic marine ecology to coastal monitoring, it is not known how accurate such morphology-based proposals are in grouping seaweeds by their form. To address this uncertainty at the foundations of seaweed biology, we surveyed and gathered all available data on seaweed forms using PRISMA protocols. We used the surface area to volume ratio (SA:V), a quantitative and universal measure of seaweed form, to assess the distribution and diversity of seaweed morphology across 99 species from three phyla. We show that seaweed surface area to volume ratio values span 3.64 orders of magnitude and follow a continuous and exponential distribution, without any significant gaps or clusters. We also tested current functional group schemes based on morphology and anatomy and showed that only 30% to 38% of their groups showed any significant pairwise differences in morphology. Our results challenge the basis of the current functional group approach in seaweed biology and suggest that a trait-based framework based on quantitative and continuous measures of seaweed form could provide a simpler and more accurate alternative to functionally assess seaweed ecology and physiology, as well as its implications for coastal ecosystem management.