Novel glycomimetic inhibitors and proteolysis-targeting chimeras for human galectins

Galectins are a family of soluble proteins that bind β-D-galactopyranoside-containing glycoconjugates through their conserved carbohydrate-recognition domains. Galectins have emerged as promising drug targets due to their involvement in various pathological conditions, such as tumor growth and metastasis, autoimmune and inflammatory diseases, as well as metabolic disorders.This first part of the thesis describes the design, synthesis, and evaluation of novel glycomimetic inhibitors of human galectin-8, which plays an essential role in pathological lymphangiogenesis, immune system modulation, bone remodeling, and is upregulated in several cancers. The structure-based design of inhibitors of galectin-8 N-terminal domain (galectin-8N) identified a benzimidazole-galactoside with a Kd of 1.8 µM for galectin-8N and 3-fold selectivity over galectin-3, and higher selectivity over the other human galectins. Molecular dynamics simulation showed that the benzimidazole-galactoside binds the non-conserved amino acid Gln47, accounting for the higher selectivity for galectin-8N. Furthermore, the subconjunctival injection of the benzimidazole-galactoside reduced the severity of bacterial keratitis caused by Pseudomonas aeruginosa in a mouse model, providing the first evidence that galectin-8 inhibitors can be effective in an actual disease model.Subsequently, we designed and synthesized a set of C-3 substituted D-galactal derivatives, which led to the discovery of a D-galactal-benzimidazole hybrid with a Kd of 48 µM for galectin-8N and 15-fold selectivity over galectin-3, and higher selectivity over the other human galectins. X-ray structural analysis of the D-galactal-benzimidazole hybrid in complex with galectin-8N followed by molecular dynamics simulation and quantum mechanical calculations showed that the high affinity of the compound for galectin-8N is probably due to the orbital overlap between the LUMO of Arg45 with the electron-rich HOMOs of the olefin and O4 of the D-galactal. A functional assay of the D-galactal-benzimidazole hybrid and the abovementioned benzimidazole-galactoside showed that both compounds reduced the secretion of the proinflammatory interleukin-6 (IL-6) and IL-8 in a dose-dependent manner. Attachment of a p-chlorophenyl moiety at C4 of the benzimidazole of the D-galactal-benzimidazole hybrid resulted in the discovery of the most potent selective galectin-8N inhibitor to date with a Kd of 2.9 µM for galectin-8N and 50-fold selectivity over galectin-3, and even higher selectivity over the other human galectins. X-ray structural analysis revealed that the high affinity of the compound for galectin-8N is probably due to the interaction of the p-chlorophenyl moiety with Arg59 and/or Tyr141 via cation-π stacking and/or π-π stacking, respectively. This compound represents a promising starting point for the design of ligands that bind galectin-8N with higher affinity and selectivity.Finally, we designed and synthesized two proteolysis-targeting chimeras (PROTACs) for human galectins to investigate whether galectins are amenable to targeted protein degradation. Although both compounds displayed nanomolar affinities for galectin-3, they failed to induce galectin-3 degradation in JIMT-1 and MDA-MB-231 breast cancer cell lines at a concentration of 25 µM. This lack of effect can be either due to the higher topological polar surface area of the compounds or the hook effect caused by the high concentration used in the assay

Do demand side variables influence financial inclusion? Lessons from South Punjab – Pakistan

Financial inclusion helps to eradicate poverty and unemployment and improves the livelihoods of the public. This research aims to examine the demand side variables that influence financial Inclusion in south Punjab, Pakistan. This research has examined the influence of education, income, accessibility, and religious belief on financial inclusion. This study has used a quantitative research design. The Likert scale questionnaire was distributed among two hundred and eighty respondents through convenience sampling.  SPSS 16 has been used for data analysis in this research. Results showed that income, education, and accessibility have a significant and positive impact on financial inclusion, but no significant relationship between religious belief and financial inclusion is found due to the availability of Islamic banking in Pakistan. This research is significant for financial inclusion policymakers and for financial institutions as it will help them to make programs to promote financial inclusion accordingly. On the supply side, a lot of work has been done but negligible work has been done on the demand side of financial inclusion. This study investigated the demand side variables that influence financial inclusion

Sharia compliance in the construction industry: is this something to build upon? / Carrie Amani Annabi, Mujtaba Ummesalma Husein, Fatima Hassan, Nouman Nasir

Sharia principles imply a mode of organising society and its various facets, as well as serving as a guide for the conduct of individuals within the institutional and social context. Accountability to be one of the pillars of environmental ethics within Islam. Another of the most important Islamic concepts is the solidarity of Islamic generations. Thus, the broader environmental dimension related to building is a social concern. Building standards need to take into account this concern for preserving sustainability for future societies. Sharia compliant projects should be permissible business. Prophet Muhammad’s (P.B.U.H.) Hadith hallmarks the significance of adhering to Islamic legislation and highlights Halal and permissible business. Therein permissible/Halal business derives its elaboration from Islamic legislation. Sharia principles are often articulated in broad terms. This has created a license to use discretion on how to apply these principles. Owing to the fact there are different schools of Islamic jurisprudence, interpretation of dicta are not always co-terminus. This paper looks into the various components particular to the discussion on Sharia compliant logistics. In order to discuss the hypothetical facets involved in the depiction of Sharia compliant logistics for construction, the discussion is broken down to address the values associated with Sharia compliant business and therefore the implications of Sharia compliant construction logistics leads on from there

Firm-Level Determinants Of Export Performance

Contribution of small and medium enterprises (SMEs) in global export is becoming significant but still a large number of these are unable to outperform in international market.  In this study, we have identified and classified the firm-level controllable determinants of export performance.  Based upon a comprehensive and systematic literature study we finally developed a synthesized model which may provide a broader understanding of the export behavior of the SMEs to enhance their export performance.  Many information sources have been explored to collect the relevant literature.  The determinants found from the literature are classified into firm’s characteristics, management characteristics, and export marketing strategic capabilities. In this paper, we have proposed a synthesized model for the researchers who are interested to investigate the issue further (i.e. about SMEs export performance determinants)

Development of A Work-based Vestibule Training E-module For Accident Prevention at Malaysian Oil and Gas Drilling Industries: A Proposed Framework

This article discusses the conceptual action plan and detailed methodology for the identification of potential hazard controls and the development of work integrated E-vestibule training module for safe onshore and offshore oil and gas drilling operation at Malaysian industries. According to the previous studies, there is a sheer industrial need of an effective work integrated vestibule training module for accident prevention at oil and gas drilling sites at Malaysian drilling domains. In this proposed study, 80 drilling crew will be randomly selected for quantitative research phase. Similarly, 03 safety experts will be purposively selected for qualitative research from each drilling domain. Whereas, for the identification of hazard controlling measures What-If analysis and thematic analysis approaches will be adopted. Furthermore, the open source vestibule training module will be developed by using ADDIE based on identified hazard controlling measures. However, the visual studio and MySQL software will use to develop the E-Module for drilling crew safety training. The proposed E-vestibule training module development framework will be used as an effective source for the elimination of life-threatening drilling hazards associated with its activities at oil and gas industries. Similarly, the proposed framework can also be implemented on other work-based learning training designs. Moreover, this proposed safety and health vestibule training module will be the first E- drilling safety module which covers all onshore and offshore drilling operation in Malaysian oil and gas extraction settings

Pharmacy Apps: a new frontier on the digital landscape?

Background: Over the course of recent years smartphone and tablet technology has evolved rapidly. Similarly, the sphere of healthcare is constantly developing and striving to embrace the newest forms of technology in order to optimise function. Many opportunities for mobile applications (i.e. ‘apps’) pertinent to the healthcare sector are now emerging.Objective: This study will consider whether registered pharmacists within the United Kingdom (UK) believe it appropriate to use mobile apps during the provision of healthcare within the community setting.Methods: Further to Liverpool John Moores University (LJMU) ethical approval, the 30 item questionnaire was distributed to UK registered pharmacists (n=600) practising within inner city Manchester, Liverpool and Newcastle. The questions were formatted as multiple choice, Likert scales or the open answer type. On questionnaire completion and return, data were analysed using simple frequencies, cross tabulations and non-parametric techniques in the Statistical Package for the Social Sciences (SPSS) (v18).Results: The majority of respondents (78.4% of 211 participants) confirmed that they were confident when using mobile apps on their technology platform. In general, mobile apps were perceived to be useful in facilitating patient consultations (55%) and supporting healthcare education (80%). The main barrier for mobile app use within the workplace was company policy, deemed significant in the case of regional / national chain pharmacies (p<0.001). Pharmacists alluded to the fact that whilst mobile apps demonstrate potential in modern day practise, they will have a greater impact in the future (p<0.001).Conclusion: The data indicate that although pharmacists are supportive of mobile apps in healthcare, a number of factors (i.e. risk, company policy and lack of regulation) may preclude their use in modern day pharmacy practise. Clearly, limitations of the technology must be addressed in order to maximise uptake within healthcare systems. Pharmacists suggest that as the younger generation ages, mobile apps will become a more accepted method by which to manage healthcare in the wider population

Examining the Influence of Adoptability, Alignment, and Agility Approaches on the Sustainable Performance of Aviation Industry: An Empirical Investigation of Supply Chain Perspective

In a continuously changing environment, the aviation sector faces the challenge of balancing adaptability to technological changes, alignment with environmental and social considerations, and agility in responding to unforeseen challenges. Keeping in view these challenges this study has explored the impact of the adaptability, alignment, and agility approaches on the sustainable performance of the aviation industry operating in Pakistan. Applying the empirical and quantitative methods the data has been collected from the professionals of the aviation industry supply chain and operations field and assessed the influence of Adoptability, Alignment, and Agility on sustainable performance indicators, including environmental stewardship, social responsibility, and economic viability. The SmartPls, structural equation model (SEM) has been applied to scrutinize the path relationships of variables. Overall the findings reveal a nuanced landscape, and it shows that traditional Adoptability may not directly impact Economic Performance (ECP), but it significantly influences Environmental (ENP), Operational (OPP), and Social Performance (SOP). Therefore, the Agility and Alignment strategies exhibit a consistent positive impact across all performance dimensions and emphasize their pivotal role in fostering holistic sustainability within the aviation sector. This study recommends that the sustainable aviation industry advocates for tailored strategies to address economic sustainability concerns, emphasizing the need for organizations to readjust their approaches. The study also highlights the vibrant nature of the aviation industry, urging continuous monitoring, evaluation, and adaptation of strategies to align with evolving sustainability paradigms. The purpose of this study and its results is to provide valuable insights for industry practitioners, policymakers, and researchers, guiding the development of strategic frameworks to enhance the long-term sustainability of the aviation industry logistics and supply chain management

Risk Appetite Discriminated Investors Wealth Accumulation: Regime-Switching versus Non-Regime-Switching Models-Based Strategies

Main objective of current research is to assess which strategy from Regime-Switching and Non-Regime-Switching Models is better for wealth accumulation by investors who are discriminated based on their risk appetite having portfolio in Sharia-Compliant cement stocks listed on PSX. The sample is consisting of 14-Sharia-Compliant cement stocks which are registered on Pakistan Stock Exchange while the daily closing balances of selected companies are retrieved from different reliable secondary sources of data for the period 18-Nov-2015 to 15-Dec-2021 and the collected data is being processed though statistical tools. The ending wealth attained through Regime-Switching Model of risk-averse investors, risk-neutral investors and risk-taker investors are 1.443, 1.340, and 1.476 respectively which are higher than attained through Non-Regime-Switching and sharp ratios are also better of all investors in RS.&nbsp; Hence, the results indicate that Regime-Switching Strategy is better than Non-Regime-Switching for wealth accumulation. This is very helpful for investors in making investment decisions wisely and policy maker in formulating of policies to rescue the investors from risk. Uniqueness of study derives from focus on risk-appetite investors wealth maximization problem, for which two entirely different models used

Critical Factors and Mitigating Measures of Construction Delays of Pakistani Building Construction Projects

 The construction industry is a significant contributor to a country's Gross Domestic Product (GDP). However, construction projects often face many issues especially delay. It is a key contributor to project failure, leading to cost overruns and a decline in quality standards. This study aims to identify the critical factors of delay in building construction projects in Pakistan, and its controlling measures of the critical delay factors. A literature review identified 48 common factors of delay in the construction industry worldwide. Based on a structured questionnaire and the average index method, 11 critical factors of delays in building construction projects in Pakistan were identified. Furthermore, a semi-structured questionnaire was used to determine 44 possible mitigation measures which were extracted from literature review with the 11 critical delay factors.  The results of this study will be useful for stakeholders in building construction projects in Pakistan. By incorporating the recommended mitigation measures, they can identify and control the most critical factors that can cause delays in building construction projects. This study contributes to the existing literature by providing a better understanding of the factors causing delays in building construction projects in Pakistan and proposing effective measures to mitigate these factors.

Perspectives of Contributing Factors and Prevention Measures of Struck-by Accidents in from Experienced Safety Personnel

Malaysia’s construction industry has been long characterized as risky, as evidenced by its poor health and safety performance. The statistics on fatal accidents recorded by the Department of Safety and Health Malaysia (DOSH) present that struck by accident in the Malaysian construction industry have the highest number of deaths and were one of the critical contributor. Therefore, this study was done to find the main contributing factor to the struck by accidents and its preventive measures. The questionnaire was distributed to the respondents, who were experienced safety personnel in construction industry with at least 10 years’ experience in handling safety and health at the workplace. From the questionnaire survey, the most significant contributing factor to struck-by accidents is careless behaviour, and the main perceived prevention measure for struck-by accident is job hazard analysis or job safety analysis briefing to workers before starting job. The outcome of the study could provide awareness on struck-by accidents and reduce the risk of struck-by accident by objects in the construction industry in Malaysia