Cystathione gamma lyase/hydrogen sulphide pathway up regulation enhances the responsiveness of ?1A and ?1B-adrenoreceptors in the kidney of rats with left ventricular hypertrophy

The purpose of the present study was to investigate the interaction between H2S and NO (nitric oxide) in the kidney and to evaluate its impact on the functional contribution of ?1A and ?1B-adrenoreceptors subtypes mediating the renal vasoconstriction in the kidney of rats with left ventricular hypertrophy (LVH). In rats the LVH induction was by isoprenaline administration and caffeine in the drinking water together with intraperitoneal administration of H2S. The responsiveness of ?1A and ?1B to exogenous noradrenaline, phenylephrine and methoxaminein the absence and presence of 5-methylurapidil (5-MeU) and chloroethylclonidine (CEC) was studied. Cystathione gamma lyase (CSE), cystathione ? synthase (CBS), 3-mercaptopyruvate sulphar transferase (3-MST) and endothelial nitric oxide synthase (eNOS) were quantified. There was significant up regulation of CSE and eNOS in the LVH-H2S compared to the LVH group (P<0.05). Baseline renal cortical blood perfusion (RCBP) was increased (P<0.05) in the LVH-H2S compared to the LVH group. The responsiveness of ?1A-adrenergic receptors to adrenergic agonists was increased (P<0.05) after administration of low dose 5-Methylurapidil in the LVH-H2S group while ?1B-adrenergic receptors responsiveness to adrenergic agonists were increased (P<0.05) by both low and high dose chloroethylclonidine in the LVH-H2S group. Treatment of LVH with H2S resulted in up-regulation of CSE/H2S, CBS, and 3-MST and eNOS/NO/cGMP pathways in the kidney. These up regulation of CSE/H2S, CBS, and 3-MST and eNOS/NO/cGMP pathways enhanced the responsiveness of ?1A and ?1B-adrenoreceptors subtypes to adrenergic agonists in LVH-H2S. These findings indicate an important role for H2S in modulating deranged signalling in the renal vasculature resulting from LVH development

A PRE-CLINICAL MODEL OF GLIOBLASTOMA RECURRENCE TO IDENTIFY PERSONALIZED THERAPEUTIC TARGETS

Glioblastoma (GBM) is the most common and lethal primary tumour affecting the central nervous system in adults. Despite aggressive, multi-modal treatment consisting of surgical resectioning of the tumour followed by radiotherapy and chemotherapy, GBM remains incurable. Almost all patients experience relapse 7-9 months post-diagnosis and median survival has not extended beyond 15 months over the past decade. Extensive research in the molecular and cellular biology of GBM has revealed extensive inter- and intra-tumoural heterogeneity caused by dysregulation at genomic, epigenomic, transcriptomic and proteomic levels. Although this has led to the identification of molecular targets for therapeutic development, large body of GBM research has focused on the study of primary GBM, with little exploration of the biological landscape of recurrent GBM. Recent genomic studies suggest that recurrent GBM evolves significantly during the course of therapy and represents a distinct biological entity and therefore therapies developed based on primary GBM biology will not present efficacy against recurrent GBM. Thus, I postulate that models that capture the evolution of GBM biology in response to standard-of-care (SoC) chemoradiotherapy will allow for the identification of therapeutic targets specific to recurrent GBM and can be used for personalized medicine. Here I show the development of an in vitro and in vivo model of GBM recurrence that can be used as a surrogate to identify personalized therapeutic targets for recurrent GBM. We use established cancer stem cell models combined with patient-derived glioblastoma stem cells (GSC) to profile and characterize the evolution of GBM through in vitro and in vivo adapted SoC. Through our in vitro model, I identified that combined chemoradiotherapy leads to increased sphere formation capacity of GBM and the global gene expression profiling of treatment-refractory GBM populations identified a poor-prognostic subtype of GBM. Next, I used patient-derived recurrent GBM to identify tyrosine kinases EphA2 and EphA3 as therapeutic targets in recurrent GBM and developed a bispecific antibody to co-target these receptors for therapeutic benefit. Lastly, I show the establishment of a novel patient-derived xenograft SoC model to profile the clonal evolution of GSCs through therapy. I show that this model can be coupled with multiple technologies, such as single cell RNA-sequencing and cellular DNA barcoding, to characterize the minimal residual cellular populations driving recurrence and identify personalized therapeutic targets for the treatment of GBM recurrence. Altogether my thesis highlights the importance of developing clinically relevant models of GBM recurrence and using poly-targeting approaches for the treatment of recurrent GBM.ThesisDoctor of Philosophy (PhD

Mechanisms of Glioma Cell Invasion

Malignant gliomas are the most aggressive primary brain tumors. Although current treatment includes surgery and chemo/radiation therapy, life expectancy remains on the order of 2 years. One of the features, which make these tumors incurable, is their infiltration into normal brain tissue. This process is incompletely understood at a molecular level and appropriate targets need to be developed. This review discusses (1) the unique structure of the neural extracellular matrix (ECM), (2) the basis of the proliferation to migration transition that initiates the infiltrative process, (3) the remodeling of the ECM by degradation and synthesis of new components, and (4) trophic factors that act as chemoattractants and chemorepellents for migrating cells. Finally we briefly discuss the challenges facing the study of this complex process and future directions in attacking this important problem in neuro-oncology

Current Trends in High-Grade Gliomas

This is an overview of the current trends in the management of high-grade gliomas based on the current evidence available at the time of compiling this chapter in the first quarter of 2016, by a dedicated, high-volume Neurosurgical Oncology team of clinical and surgical Neuro-Oncologists based in central Pennsylvania

Examining consequences of brand hate in business-to-business relationships : The moderating role of relationship length

This study advances the ongoing scholarly research on brand hate discourse by investigating its consequences in the business-to-business (B2B) context – thereby attempting to initiate a novel trajectory in brand hate literature by including the B2B perspective. The paper demonstrates and validates a conceptual model that connects brand hate with complaining (an immediate behavior), boycott, and retaliation (next stage behaviors) adopted by business buyers with varying relationship lengths with the selling brand. Based on two empirical studies, a survey, and a scenario-based quasi-experiment, results demonstrate that aggressive behaviors of business customers are associated with buyers’ emotional processes (hate). In particular, it confirms the direct effect of brand hate on complaining, boycott, and retaliation. Further, it demonstrates the mediation mechanism of complaining between hate-boycott and hate-retaliation relationships. Interestingly, these effects are more substantial for customers with longer relationship length. The findings enrich B2B literature on negative customer-brand relationships and provide managerial guidance for devising strategies to cope with brand hate and unfavorable consequential behaviors

An empirical examination of brand hate influence on negative consumer behaviors through NeWOM intensity. Does consumer personality matter?

Limited research has investigated the consequences of brand hate, particularly the pathways and contingent factors. This study addresses a critical gap by investigating the mediation of negative electronic word-of-mouth (NeWOM) intensity between brand hate and the two different forms of consumers’ coping behaviors: boycott (instrumental aggression) and brand sabotage (hostile aggression). It also demonstrates the moderating role of the Big Five personality traits in these pathways. An empirical survey with 391 participants recruited through Prolific reveals that brand hate directly affects NeWOM intensity, consumer boycott, and brand sabotage. These effects are more substantial for those who score high in neuroticism, extraversion, and conscientiousness. On the other hand, the effects of brand hate on NeWOM intensity and boycott are more profound when agreeableness is low. In contrast, only brand hate-to-boycott relationship strengthens when openness is low. Interestingly, NeWOM intensity mediates the relationships between brand hate and the two consumer behaviors, i.e., consumer boycott and brand sabotage. These findings enrich the literature on negative consumer-brand relationships and provide managers assistance in developing effective strategies for de-escalating consumers’ use of aggressive behaviors in response to brand hate

Malnutrition’s Prevalence and Associated Factors

Malnutrition, which affects roughly 2 billion people worldwide, is among the country’s most pressing health issues. In comparison to other developing nations, Pakistan has one of the worst prevalence of childhood malnutrition. We’ll explore how people in poor countries manage food scarcity. Owing to low per capita income and a lack of purchasing power for fundamental food staples that meet the human body’s nutritional demands. Malnourished children in Pakistan suffer from stunting, wasting, and being underweight. The causes of child malnutrition and stunting in Pakistan are discussed in this chapter, as well as the impact of numerous factors on stunting and the types of intervention methods and practices that should be devised and executed to address the problem

Mixotrophic cultivation of Scenedesmus dimorphus in sugarcane bagasse hydrolysate

Overuse of the fossil fuels to fulfill existing energy requirements has generated various environmental problems like global warming. Emergence of environmental issues due to burning of the fossil fuel resources has provoked researchers to explore alternative sources of fuel. In this scenario, microalgal biofuels could present a promising alternative fuel if produced cost-effectively without competing for freshwater resources and arable land. Aim of the present study was to grow microalgae by employing lignocellulosic waste for production of lipids. Scenedesmus dimorphus NT8c was chosen based on its ability to tolerate heat, rapid growth, and ease of harvesting by overnight settling. Biochemical composition and growth parameters of microalgae were analyzed when cultivated mixotrophically on sugarcane bagasse hydrolysate, a low-value agricultural by-product, that is, currently underutilized. Despite a slight increase in turbidity in the medium, S. dimorphus NT8c cultures raised mixotrophically in 5 g/L sugarcane bagasse hydrolysate displayed significantly higher growth rates compared to photoautotrophic cultivation with an overall biomass productivity of 119.5 mg L d, protein contents of 34.82% and fatty acid contents of 15.41%. Thus, microalgae cultivated mixotrophically are capable of photosynthesizing while metabolizing and assimilating organic carbon, significant increases of biomass and lipid productivity can be achieved. However, high supplementation with organic carbon can result in unfavorable levels of turbidity and bacterial growth, reducing microalgal biomass productivity

Comparison of Quantitative C-Reactive Protein with Blood Lactate Levels as Septic Markers in Neonatal Sepsis: A Cross-Sectional Study in a Tertiary Care Setting, Peshawar

Objective: To find the relationship between the quantitative C-reactive protein and lactate as septic markers in neonatal sepsis. Study Design: Cross-sectional study. Place and Duration of Study: This study was conducted at the Neonatal Intensive Care Unit of Combined Military Hospital (CMH), Peshawar, Pakistan from March 2024 to August 2024. Methods: Neonates (age 1 day–28 days) diagnosed with sepsis were enrolled. Patients were categorized into two groups: Group I (Survivors) and Group II (Non-survivors). Patient's demographic details, blood cultures, serum C-reactive protein, neutrophil counts, plasma Lactate, and outcome in terms of hospital discharge were assessed and recorded. Data analysis was done using SPSS version 26. Results: Of the total 136 neonates, there were 76 (55.9%) male and 60 (44.1%) female. The overall mean age was 14.56±7.82 days. Group I had 92 (67.6%) survivors and Group II had 44 (32.4%) non-survivors. The median value of Lactate (millimole/Liter) and C-reactive protein (milligram/deciliter) was 2.3 (IQR 1.4-5.3) and 2.1 (IQR 0.15-8.7), respectively. Survivor group (Group-I) had lower Lactate (1.9 millimole/Liter [1.2–9] than the nonsurvivor group (4.5 millimole/Liter [2.15–7.4]), P < 0.05. The prevalence of multiple organ dysfunction was significantly higher in Group-II 82 (89.1%) than in Group-I 16 (36.4%). Based on organism causing infections among 136 neonatal sepsis cases, the incidence of Group B Streptococcus, Escherichia coli, Listeria monocytogenes, Coagulase-Negative Staphylococci, Staphylococcus aureus, Enterococcus species, Klebsiella species, and Pseudomonas aeruginosa was 58 (43%), 32 (24%), 9 (7%), 7 (5%), 4 (3%), 14 (10%), 10 (7%), and 2 (1%), respectively. Conclusion: Lactate is superior to C-reactive protein in predicting prognosis and mortality in neonatal sepsis in the Neonatal intensive care unit. Elevated levels of lactate and C-reactive protein are primarily associated with increased severity of neonatal sepsis, including the progression to multiple organ dysfunction syndrome (MODS), septic shock, and poor clinical outcomes. How to cite this: Ali F, Aqib AR, Ahmad N, Ibrahim S, Rehman M, Usman A. Comparison of Quantitative C-Reactive Protein with Blood Lactate Levels as Septic Markers in Neonatal Sepsis: A Cross-Sectional Study in a Tertiary Care Setting, Peshawar. Life and Science. 2025; 6(3): 310-316. doi: http://doi.org/10.37185/LnS.1.1.74

The Effect of Foreign Direct Investment on the Nexus between Green Levies and Green Energy Technologies

Exploring the role of foreign direct investment (FORGDIR) in promoting the influence of green levies (GRENLEV) on green energy technologies (GETs) is pivotal for achieving sustainable development goals. This study therefore, explores the influence of FORGDIR on the nexus between green levies (GRENLEV) and green energy technologies (GETs). We employed quantitative research paradigm as we extracted data from the quantitative method. Data was extracted from the World Bank Database and “Organisation for Economic Co-operation and Development” (OECD) for 20 years from 2003 to 2022 relating to Nigeria. After controlling for climate change and greenhouse emanations, the study found that GRENLEV is positive and significantly related to GETs. It was also revealed that FORGDIR is negative and significantly GETs. It was finally documented that the interaction between FORGDIR and GRENLEV (GREENT*FDI) is negative and significantly related to GETs, implying that FORGDIR reverses the positive effect of GRENLEV on GETs. Thus, it requires a careful policy design and regulatory frameworks that align FORGDIR with green objectives which in return stimulate sustainable investment in GETs. Therefore, this study can provide a useful information for the policymakers and regulators in providing strategies for green growth and sustainable development goals