Discrete Roles Research Articles

PD-L2 act as an independent immune checkpoint in colorectal cancer beyond PD-L1

IntroductionImmunotherapy, especially immune checkpoint blockade (ICB), holds promise as a therapeutic strategy in colorectal cancer (CRC) by harnessing the patient’s immune system to target malignant cells. Particularly, the PD-1/PD-L1 axis is widely recognized for its critical role in tumor microenvironment immunosuppression. Antibodies targeting PD-1 or PD-L1 have shown sustained efficacy against various cancers, including CRC. Nonetheless, many CRC patients exhibit limited responses to such immunotherapy, and the resistance mechanisms remain incompletely understood.MethodsWe conducted experiments with C57BL/6 mice, and used the MC38 cell line for ICB treatment studies in syngeneic mouse models. Gene and protein analyses were performed using qPCR, Western Blot, and flow cytometry, with bioinformatics for clinical data survival analysis.ResultsIn this study, we reveal that targeting PD-L2 emerges as a complementary therapeutic strategy to PD-1/PD-L1 blockade in CRC. Although PD-L2 is also inducible by IFNγ, like PD-L1, it displays a unique spatial distribution within the tumor microenvironment, implying discrete roles in immune evasion. Additionally, we uncovered a significant correlation between PD-L1 and PD-L2 expression levels and the infiltration of various immune cells, encompassing multiple dendritic cell (DC) subtypes. This correlation implies an enhanced antigen presentation process that may be unleashed by blocking these two immune checkpoints.DiscussionOur results highlight the significance of PD-L2 as an essential immune checkpoint alongside PD-L1 and emphasize its potential as a target for bolstering antitumor immunity in colorectal cancer.

Immunoglobulin A Antibodies: From Protection to Harmful Roles.

Immunoglobulin A (IgA) is the most abundantly produced antibody in humans. IgA is a unique class of immunoglobulin due to its multiple molecular forms, and a defining difference between the two subclasses: IgA1 has a long hinge-region that is heavily O-glycosylated, whereas the IgA2 hinge-region is shorter but resistant to bacterial proteases prevalent at mucosal sites. IgA is essential for immune homeostasis and education. Mucosal IgA plays a crucial role in maintaining the integrity of the mucosal barrier by immune exclusion of pathobionts while facilitating colonization with certain commensals; a large part of the gut microbiota is coated with IgA. In the circulation, monomeric IgA that has not been engaged by antigen plays a discrete role in dampening inflammatory responses. Protective and harmful roles of IgA have been studied over several decades, but a new understanding of the complex role of this immunoglobulin in health and disease has been provided by recent studies. Here, we discuss the physiological and pathological roles of IgA with a special focus on the gut, kidneys, and autoimmunity. We also discuss new IgA-based therapeutic approaches.

Narcissistic Chief Executive Officers and Their Effects on R&D Investment and Firm Performance: The Moderating Role of Managerial Discretion.

The impact of the chief executive officer (CEO) narcissism on a firm's performance has gained attention from the academic community. However, the extant literature has largely ignored the mediating mechanism of research and development (R&D) investment and the moderating roles of managerial discretion. Additionally, the measurement of CEO narcissism is rarely disclosed in the public database. Compiling a CEO narcissism index from a video survey, we systematically explore the effect of CEO narcissism on firm performance, the mediating role of R&D investment, and the moderating role of managerial discretion. Based on the upper echelons theory, using a sample of 183 Chinese A-share listed manufacturing firms from 2011 to 2019, we found that CEO narcissism positively and significantly impacts R&D investment and firm performance, and then R&D investment mediated the relationships between CEO narcissism and firm performance. In addition, we found that managerial discretion could affect the relationship between CEO narcissism and R&D investment. Specifically, CEO duality and CEO ownership will strengthen the positive influence of a CEO's narcissism in corporate R&D investment. Our results suggest that CEO narcissism appears to be a stimulus to corporate R&D investment; thus, in recruiting top executives, their psychological traits, especially narcissism, should be given special consideration.

Top management team attributes and corporate entrepreneurship: A meta‐analysis

AbstractHow do the attributes of a firm's top management team (TMT) influence corporate entrepreneurship across organizational and national contexts? Drawing on upper echelons theory and the managerial discretion perspective, this meta‐analytic study examines the dynamic relationship between TMTs' attributes and corporate entrepreneurship, focusing on the moderating role of managerial discretion arising from organizational and national‐level factors. To provide insights into the micro‐foundations of firm behavior, we explore how key TMT attributes—diversity, size, transformational leadership, tenure, general human capital, and entrepreneurial human capital—affect corporate entrepreneurship. A comprehensive meta‐analysis of 57 primary studies reveals that the effect of a TMT's attributes is context‐dependent and is significantly influenced by the approach to managerial discretion taken by the country in which the firm operates. By showing that transformational leadership and the TMT's entrepreneurial human capital and size affect corporate entrepreneurship, while attributes like tenure, diversity, and general human capital have limited or no impact, our findings challenge the prevailing view that a standardized approach to the TMT's composition drives corporate entrepreneurship. The study also underscores the role of the national‐level managerial discretion and finds that firms in institutional environments that feature low managerial discretion must align their TMT strategies with local institutional contexts to maximize their corporate entrepreneurship. These findings advance upper echelons theory by demonstrating that managerial discretion acts as a boundary condition in shaping how the TMT's attributes influence corporate entrepreneurship based on the national context. This research contributes to the fields of strategic and innovation management and offers practical insights for leaders who seek to harness the full potential of their TMTs.

Reforming Post-Arrest Bail in Pakistan: Lessons from a Comparative Study with India

This research paper presents a comparative analysis of the legal frameworks governing post-arrest bail in India and Pakistan, with a focus on the statutory provisions, judicial interpretations, and procedural safeguards that are involved. Although both states share a common legal heritage which is rooted in British colonial law, however, they have diverged in their approaches to bail, which are influenced by their respective constitutional mandates, legislative developments, and sociopolitical landscapes. This comparison is essential in order to understand how these legal systems are balancing individual rights with societal security and how judicial discretion are shaping bail in each country. For this purpose, this paper examines constitutional provisions besides main statutory provisions of the Indian and Pakistani criminal procedural laws, the role of judicial discretion and evolving jurisprudence of the post-arrest bail. This study offers insights into potential legal reforms, with an aim to enhance fairness and consistency in bail practices, through juxtaposing these principles in India and Pakistan. This study concludes that Pakistan should consider restructuring its bail procedural laws and system, and it suggests reforms taking into account the benefits of India’s progressive legal framework, to ensure consistency, fairness, and the protection of individual rights. This research also recommends future studies on balancing bail and incarceration, through focusing on judicial discretion and the application of the principle of proportionality.

Corticospinal and corticoreticulospinal projections have discrete but complementary roles in chronic motor behaviors after stroke.

After corticospinal tract (CST) stroke, several motor deficits can emerge in the upper extremity (UE), including diminished muscle strength, motor control, and muscle individuation. Both the ipsilesional CST and contralesional corticoreticulospinal tract (CReST) innervate the paretic UE, but their relationship to motor behaviors after stroke remains uncertain. In this cross-sectional study of 15 chronic stroke and 28 healthy subjects, we examined two questions: whether the ipsilesional CST and contralesional CReST differentially relate to chronic motor behaviors in the paretic arm and hand, and whether the severity of motor deficits differ by proximal versus distal location. In the paretic biceps and first dorsal interosseous muscles, we therefore used transcranial magnetic stimulation to measure the projection strengths of the ipsilesional CST and contralesional CReST. We also used quantitative testing to measure strength, motor control, and muscle individuation in each muscle. Stroke subjects had comparable muscle strength to healthy subjects but poorer motor control and muscle individuation. In both muscles, stronger ipsilesional CST projections related to better motor control, whereas stronger contralesional CReST projections related to better muscle strength. Stronger CST projections related to better individuation in the biceps alone. The severity of motor control and individuation deficits was comparable in the arm and hand. These findings suggest that the ipsilesional CST and contralesional CReST have specialized but complementary roles in motor behaviors of the paretic arm and hand. They also suggest that deficits in motor control or muscle individuation are not segmentally biased, underscoring the functional reach and efficacy of the pathways.

Aerodynamic investigation of an S-shaped intake employing sweeping jet actuators based on proper orthogonal decomposition

The central curvature change of the S-shaped intake exacerbates the three-dimensional flow separation, resulting in total pressure and swirl distortions at the outlet. In this paper, an efficient active flow control technique, the sweeping jet actuator, was applied to control flow separation. The instantaneous characteristics of the flow field inside and outside the actuator were revealed by using validated numerical simulation methods. In addition, the effect of the sweeping jet on the aerodynamic performance of the S-shaped intake was investigated. Proper orthogonal decomposition (POD), an analysis method used to extract the main feature components of data, was applied to decompose the flow field structure at the S-shaped intake outlet in this study. The results highlight the external flow field characteristics of the actuator, with a jet sweeping range of up to ±40° and a sweeping frequency of 1 500 Hz, corresponding to a Strouhal number of 0.018. When the jet momentum coefficient is only 0.116%, the total pressure loss coefficient and pressure distortion index are reduced by 5.6% and 24.76%, respectively. This study demonstrates the critical role of momentum injection and discretization in inhibiting flow separation in the channel. The POD-based analysis indicates that a sweeping jet with high momentum can significantly enhance the energy in the flow passage and reduce the vorticity intensity of the first three modes. The stable mode structures exist near the outlet, exhibiting excitation frequency and frequency-doubling properties. The findings of this research provide essential input conditions for subsequent distortion studies.

The role of discretion and street‐level deliberative practices in the COVID‐19 crisis response: Lessons from the Philippines

AbstractThis study investigates the role of frontline workers, such as the Barangay Health Emergency Response Teams (BHERTs) in the Philippines, as street‐level bureaucrats (SLBs) in implementing COVID‐19 community quarantine policies. Drawing from SLB theory and deliberative policy analysis (DPA), I explore how SLBs adapted to rapidly changing conditions by exercising discretion in interpreting and adapting the implementation of nationally formulated pandemic management policies to meet local realities. I argue that SLBs functioned as deliberative practitioners, mediating between national policies and local realities while engaging in deliberative practices with their clients. Using the experience of BHERTs in Palompon, Leyte in the Philippines as an illustrative case, I identified the policy mandates (policy‐as‐written) of the BHERTs; the challenges and constraints they faced in implementing community quarantine policies; and the discretion they exercised in implementing community quarantine policies (policy‐as‐practiced). The findings reveal that, to meet their policy mandates and address the challenges they faced, they engaged in deliberative practices and collaborated with citizens in implementing context‐specific and creative strategies. Insights from this study highlight the adaptive and deliberative potential of SLBs in crisis situations and the value of a DPA in understanding SLB theory and research. By examining SLBs’ experiences during the pandemic, this study contributes to the SLB literature and offers practical lessons to policy practitioners in facilitating deliberation and developing context‐specific solutions in times of crisis.Points for practitioners The COVID‐19 pandemic and the subsequent government response in the Philippines have increased the challenges faced by street‐level bureaucrats (SLBs), including resource scarcity, organisational and political pressure, public resistance, and the risk of exposure to the virus. SLBs have shown their capacity to apply discretion and collaborate with their clients to resolve their own and the client's challenges and limitations through negotiation, mediation, conflict management, and active listening. This cooperative approach empowers them to resolve common issues and together formulate effective strategies that are beneficial to all parties involved. Relationships outside of SLBs’ duties as state agents (i.e. socio‐cultural relationships) can be a viable pathway for SLBs to implement alternative policy strategies to meet their policy mandates and address the challenges they face as they implement their mandates. Competing value systems, knowledge claims, and emotional narratives, compounded by a governance crisis, define the complex and informal nature of the policy process in the context of a crisis like the pandemic. Although SLBs demonstrate their capacity to creatively solve the challenges they encounter through deliberative practices, this should not serve as a justification for the government's lack of action in prioritising, safeguarding, and preserving their welfare.

Manager political preferences and company investor bases

AbstractWe investigate how the personal political preferences of top managers shape the investor base of firms. Based on the risk‐aversion attitude of firm decisions that rely on conservative political ideologies, we find that Republican managers tend to maintain a lower leverage level; invest less in tangible assets and R&D to pursue near‐term profitability; and maintain a high quality of information disclosure to increase stock liquidity. We demonstrate that firms led by Republican managers can attract more transient institutions. This relationship becomes stronger during financially stressful periods and is robust after considering the moderating role of managerial discretion and potential endogeneity.

Conserved 5-methyluridine tRNA modification modulates ribosome translocation

While the centrality of posttranscriptional modifications to RNA biology has long been acknowledged, the function of the vast majority of modified sites remains to be discovered. Illustrative of this, there is not yet a discrete biological role assigned for one of the most highly conserved modifications, 5-methyluridine at position 54 in tRNAs (m5U54). Here, we uncover contributions of m5U54 to both tRNA maturation and protein synthesis. Our mass spectrometry analyses demonstrate that cells lacking the enzyme that installs m5U in the T-loop (TrmA in Escherichia coli, Trm2 in Saccharomyces cerevisiae) exhibit altered tRNA modification patterns. Furthermore, m5U54-deficient tRNAs are desensitized to small molecules that prevent translocation in vitro. This finding is consistent with our observations that relative to wild-type cells, trm2Δ cell growth and transcriptome-wide gene expression are less perturbed by translocation inhibitors. Together our data suggest a model in which m5U54 acts as an important modulator of tRNA maturation and translocation of the ribosome during protein synthesis.

HLTF resolves G4s and promotes G4-induced replication fork slowing to maintain genome stability

G-quadruplexes (G4s) form throughout the genome and influence important cellular processes. Their deregulation can challenge DNA replication fork progression and threaten genome stability. Here, we demonstrate an unexpected role for the double-stranded DNA (dsDNA) translocase helicase-like transcription factor (HLTF) in responding to G4s. We show that HLTF, which is enriched at G4s in the human genome, can directly unfold G4s invitro and uses this ATP-dependent translocase function to suppress G4 accumulation throughout the cell cycle. Additionally, MSH2 (a component of MutS heterodimers that bind G4s) and HLTF act synergistically to suppress G4 accumulation, restrict alternative lengthening of telomeres, and promote resistance to G4-stabilizing drugs. In a discrete but complementary role, HLTF restrains DNA synthesis when G4s are stabilized by suppressing primase-polymerase (PrimPol)-dependent repriming. Together, the distinct roles of HLTF in the G4 response prevent DNA damage and potentially mutagenic replication to safeguard genome stability.

What is the Quality for Carbon Disclosure? The Role of Managerial Discretion and Governance

What is the Quality for Carbon Disclosure? The Role of Managerial Discretion and Governance

The Tightrope of Individual Liberties amid Pakistan’s Counter-Terrorism Agenda

This doctrinal research article explores the nuances, pitfalls, and opportunities within this intricate landscape. This doctrinal research delves into the intricate balance between individual liberties and Pakistan's counter-terrorism agenda, navigating the complex terrain where security imperatives intersect with fundamental rights. As Pakistan grapples with persistent security threats from terrorism, its response has often entailed the implementation of stringent measures aimed at thwarting terrorist activities and ensuring public safety. However, these measures have raised concerns about their impact on civil liberties, including freedoms of expression, association, and privacy. Drawing upon legal frameworks, policy documents, and judicial precedents, this research critically examines the evolving landscape of counter-terrorism laws and practices in Pakistan and their implications for individual liberties. It scrutinizes the compatibility of counter-terrorism measures with constitutional guarantees and international human rights standards, assessing the extent to which security imperatives have encroached upon fundamental rights and freedoms. Furthermore, this research explores the role of judicial oversight, executive discretion, and legislative reforms in reconciling the tension between security concerns and individual liberties within Pakistan's legal framework. It analyses landmark court decisions, legislative enactments, and government policies to elucidate the legal and institutional mechanisms aimed at safeguarding individual liberties while countering terrorism effectively. Moreover, this research situates Pakistan's counter-terrorism efforts within the broader context of regional security dynamics, highlighting the interconnectedness of domestic security challenges with regional conflicts, geopolitical rivalries, and transnational terrorist networks. It underscores the importance of regional cooperation, information sharing, and diplomatic engagement in addressing common security threats while respecting individual liberties across borders. By critically examining the tightrope walk between individual liberties and Pakistan's counter-terrorism agenda, this research contributes to a nuanced understanding of the challenges and trade-offs inherent in balancing security imperatives with respect for fundamental rights.

CD11c-expressing microglia are transient, driven by interactions with apoptotic cells.

Microglia, the parenchymal macrophage of the central nervous system serve crucial remodeling functions throughout development. Microglia are transcriptionally heterogenous, suggesting that distinct microglial states confer discrete roles. Currently, little is known about how dynamic these states are, the cues that promote them, or how they impact microglial function. In the developing retina, we previously found a significant proportion of microglia express CD11c (Integrin αX, complement receptor 4, Itgax) which has also been reported in other developmental and disease contexts. Here, we sought to understand the regulation and function of CD11c+ microglia. We found that CD11c+ microglia track with prominent waves of neuronal apoptosis in postnatal retina. Using genetic fate mapping, we provide evidence that microglia transition out of the CD11c state to return to homeostasis. We show that CD11c+ microglia have elevated lysosomal content and contribute to the clearance of apoptotic neurons, and found that acquisition of CD11c expression is, in part, dependent upon the TAM receptor Axl. Using selective ablation, we found CD11c+ microglia are not uniquely critical for phagocytic clearance of apoptotic cells. Together, our data suggest CD11c+ microglia are a transient state induced by developmental apoptosis rather than a specialized subset mediating phagocytic elimination.

Selective estrogen receptor activation prior to global cerebral ischemia in female rats impacts microglial activation and anxiety-like behaviors without effects on CA1 neuronal injury

Estrogen receptor (ER) activation by 17-ß estradiol (E2) can attenuate neuronal injury and behavioral impairments following global cerebral ischemia (GCI) in rodents. This study sought to further examine the discrete roles of ERs through characterization of the effects of selective ER activation on post-ischemic pro-inflammatory microglial activation, hippocampal neuronal injury, and anxiety-like behaviors. Forty-six ovariectomized (OVX) adult female Wistar rats received daily s.c injections (100 μg/kg/day) of propylpyrazole triol (PPT; ERα agonist), diarylpropionitrile (DPN; ERβ agonist), G-1 (G-protein coupled ER agonist; GPER), E2 (activating all receptors), or vehicle solution (VEH) for 21 days. After final injection, rats underwent GCI via 4-vessel occlusion (n=8 per group) or sham surgery (n=6, vehicle injections). The Open Field Test (OFT), Elevated Plus Maze (EPM), and Hole Board Test (HBT) assessed anxiety-like behaviors. Microglial activation (Iba1, CD68, CD86) in the basolateral amygdala (BLA), CA1 of the hippocampus, and paraventricular nucleus of the hypothalamus (PVN) was determined 8 days post-ischemia. Compared to sham rats, Iba1 activation and CA1 neuronal injury were increased in all ischemic groups except DPN-treated rats, with PPT-treated ischemic rats also showing increased PVN Iba1-ir expression. Behaviorally, VEH ischemic rats showed slightly elevated anxiety in the EPM compared to sham counterparts, with no significant effects of agonists. While no changes were observed in the OFT, emotion regulation via grooming in the HBT was increased in G-1 rats compared to E2 rats. Our findings support selective ER activation to regulate post-ischemic microglial activation and coping strategies in the HBT, despite minimal impact on hippocampal injury.

The impact of the interaction of independent and cooperative innovation on firm digitization: the moderating role of managerial discretion

PurposeThis study aims to deliver a new perspective on how the interaction of independent and cooperative innovation affects firm digitization. Based on resource constraint theory, this study argues that the aforementioned interaction negatively affects firm digitization. The moderating role of managerial discretion is also discussed in light of the principles of the awareness-motivation-capability (AMC) framework.Design/methodology/approachThe proposed hypotheses are empirically tested using a negative binomial modeling approach. The data used are from A-share listed companies in China’s Shanghai and Shenzhen stock markets from 2006 to 2020.FindingsThis study suggests that the interaction of independent innovation and cooperative innovation negatively impacts digitization. In addition, this study argues that environmental discretion and organizational discretion weaken the negative impact of the mentioned interaction on digitization. However, additional discretion in the Chinese context has no effect on above relationships.Originality/valueThis study explores the impact of the interaction of independent and cooperative innovation on digitization and incorporates managerial discretion into this framework based on the AMC framework.

The role of administrative discretion in the coping behaviour of street-level bureaucrats in higher education institutions of Pakistan

Policies are created at the highest level, and street-level bureaucrats (SLBs) implement them at lower levels. SLBs work directly with citizens and exercise significant discretion in their service. According to Lipsky's theory, SLBs face various problems and use multiple coping techniques to deal with them. This study focused on the discretionary powers of the heads of departments (HODs) and the use of coping mechanisms when faced with challenges in enacting the semester system policy. The existing study used the theoretical model of coping mechanisms using a single-case research methodology to investigate the HODs of a prestigious public university's coping behaviour in implementing the semester system. Semi-structured interviews were employed to get the perspectives of HODs in this qualitative research. This study used the classification model of coping families developed by Tummers, Bekkers, Vink, and Michael (2015) and concludes that management has given HODs some task-discretionary authority for carrying out the semester system policy based on thematic analysis. The findings reveal that HODs move against the students rather than towards or away from them in coping behaviour. HODs strictly follow the semester system's policy by adhering to rigid rule-following.

An improve unsupervised discretization using optimization algorithms for classification problems

This paper addresses the classification problem in machine learning, focusing on predicting class labels for datasets with continuous features. Recognizing the critical role of discretization in enhancing classification performance, the study integrates equal width binning (EWB) with two optimization algorithms: the bat algorithm (BA), referred to as EB, and the whale optimization algorithm (WOA), denoted as EW. The primary objective is to determine the optimal technique for predicting relevant class labels. The paper emphasizes the significance of discretization in data preprocessing, offering a comprehensive approach that combines discretization techniques with optimization algorithms. An investigative study was undertaken to assess the efficiency of EB and EW by evaluating their classification performance using Naive Bayes and K-nearest neighbor algorithms on four continuous datasets sourced from the UCI datasets. According to the experimental findings, the suggested EB has a major effect on the accuracy, recall, and F-measure of data classification. The classification performance using EB outperforms other existing approaches for all datasets.

Age influences CMV-specific NK and CD8 T cell memory fates

Abstract Cytomegalovirus (CMV), a prevalent persistent infection often unnoticed in healthy adults, is the most common congenital infection of neonates/ infants. NK cells and CD8 T cells control CMV via cytolysis of infected cells; yet their coordinate response to CMV remains uncharacterized, particularly in infants. We interrogated how NK and CD8 T cell responses differed between adults and infants in a murine CMV (MCMV) infection model. Infant mice had higher viral burden and delayed viral clearance in multiple tissues. T cell depletion enhanced infant MCMV-induced morbidity; yet, co-adoptive transfer of adult and infant OT-I CD8 T cells followed by MCMV-OVA infection revealed phenotypic and transcriptional limits in infant T cell capacity to form memory precursors and subsequent memory. This impairment was age-dependent, co-transfer of OT-I cells from sequentially aged mice had increasing memory formation, overall infant CD8 T cells are effector biased with limited memory potential. To reconcile how infants bridge this gap in T cell immunity we interrogated NK cell responses. Unlike adult mice, infant Ly49H+ (MCMV-specific) NK cells potently responded to infection, adopting an effector-memory (KLRG1+CD62L+) phenotype. Notably, loss of memory NK cells with age coincided with the increasing OT-I memory potential. Our data suggest discrete roles for NK cells and CD8 T cells in MCMV infection during infancy with NK cells as key responders prior to T cell ability to acquire memory.

Insights into the ATP / GTP selectivity of a GTPase, adenylosuccinate synthetase from Leishmania donovani

Many GTPases have been shown to utilize ATP too as the phosphoryl donor. Both GTP and ATP are important molecules in the cellular environments and play multiple and discrete functional role within the cells. In our present study, we showed that one of the purine metabolic enzymes Adenylosuccinate synthetase from Leishmania donovani (LdAdSS) which belongs to the BioD-superfamily of GTPases can also carry out the catalysis by hydrolysing ATP instead of its cognate substrate GTP albeit with less efficiency. Biochemical and biophysical studies indicated its ability to bind to ATP too but at a higher concentration of ATP compared to that of GTP. Sequence analysis and molecular dynamic simulations suggested that residues of the switch loop and the G4-G5 (593SAXD596) connected motif of LdAdSS plays a role in determining the nucleotide specificity. Though the crucial interaction between Asp596 and the nucleotide is broken when ATP is bound, interactions between the Ala594 and the adenine ring of ATP could still hold ATP in the GTP binding site. The results of the present study suggested that though LdAdSS is GTP specific, it still shows ATP hydrolysing activity.