Restricted Entry Research Articles

Nose to brain delivery of Rotigotine loaded solid lipid nanoparticles: Quality by design based optimization and characterization

Rotigotine (RTG), for the treatment of Parkinson disease has low oral bioavailability (1–5%) due to its high gut clearance and restricted entry by brain barriers.RTG is dopamine (D1-D5) &5HT1A agonist and α-2 adrenergic receptors antagonist. In present research, RTG loaded Solid Lipid Nanoparticles (RTG-SLNs) was optimized to improve bioavailability via. nose to brain delivery. Quality by Design approach for the product development was used. Dynasan 118 as solid lipid and tween 80 as surfactant were optimized. RTG-SLNs were prepared by hot melt emulsification method using high speed homogenizer. Amongst various independent variables, critical variables were selected using 25−2 Fractional Factorial Design. Further optimization was done using central composite design. Design results were analyzed using ANOVA, Pareto chart, surface plots and desirability. Optimized RTG-SLNs gave desired particle size (129 nm), % Entrapment Efficiency (83%), Polydispersivity index (0.285), zeta potential (−23.1) and in-vitro drug release in phosphate buffer 7.4 for 30 h (99%). Further optimized batch was characterized using FTIR, TEM and AFM. From the ex-vivo permeability, cellular uptake study (confocal laser scanning microscopy) and histopathology study, RTG-SLNs was found permeable through goat nasal mucosa and non-toxic. Formulation was found stable during 3 months’ stability studies at refrigerated condition.

C4b Binding Protein Acts as an Innate Immune Effector Against Influenza A Virus.

C4b Binding Protein (C4BP) is a major fluid phase inhibitor of the classical and lectin pathways of the complement system. Complement inhibition is achieved by binding to and restricting the role of activated complement component C4b. C4BP functions as a co-factor for factor I in proteolytic inactivation of both soluble and cell surface-bound C4b, thus restricting the formation of the C3-convertase, C4b2a. C4BP also accelerates the natural decay/dissociation of the C3 convertase. This makes C4BP a prime target for exploitation by pathogens to escape complement attack, as seen in Streptococcus pyogenes or Flavivirus. Here, we examined whether C4BP can act on its own in a complement independent manner, against pathogens. C4BP bound H1N1 and H3N2 subtypes of Influenza A Virus (IAV) most likely via multiple sites in Complement Control Protein (CCP) 1-2, 4-5, and 7-8 domains of its α-chain. In addition, C4BP CCP1-2 bound H3N2 better than H1N1. C4BP bound three IAV envelope proteins: Haemagglutinin (~70 kDa), Neuraminidase (~55 kDa), and Matrix protein 1 (~25kDa). C4BP suppressed H1N1 subtype infection into the lung epithelial cell line, A549, while it promoted infection by H3N2 subtype. C4BP restricted viral entry for H1N1 but had the opposite effect on H3N2, as evident from experiments using pseudo-typed viral particles. C4BP downregulated mRNA levels of pro-inflammatory IFN-α, IL-12, and NFκB in the case of H1N1, while it promoted a pro-inflammatory immune response by upregulating IFN- α, TNF-α, RANTES, and IL-6 in the case of H3N2. We conclude that C4BP differentially modulates the efficacy of IAV entry, and hence, replication in a target cell in a strain-dependent manner, and acts as an entry inhibitor for H1N1. Thus, CCP containing complement proteins such as factor H and C4BP may have additional defense roles against IAV that do not rely on the regulation of complement activation.

Cell-penetrating peptides (CPPs): an overview of applications for improving the potential of nanotherapeutics.

In the field of nanotherapeutics, gaining cellular entry into the cytoplasm of the target cell continues to be an ultimate challenge. There are many physicochemical factors such as charge, size and molecular weight of the molecules and delivery vehicles, which restrict their cellular entry. Hence, to dodge such situations, a class of short peptides called cell-penetrating peptides (CPPs) was brought into use. CPPs can effectively interact with the cell membrane and can assist in achieving the desired intracellular entry. Such strategy is majorly employed in the field of cancer therapy and diagnosis, but now it is also used for other purposes such as evaluation of atherosclerotic plaques, determination of thrombin levels and HIV therapy. Thus, the current review expounds on each of these mentioned aspects. Further, the review briefly summarizes the basic know-how of CPPs, their utility as therapeutic molecules, their use in cancer therapy, tumor imaging and their assistance to nanocarriers in improving their membrane penetrability. The review also discusses the challenges faced with CPPs pertaining to their stability and also mentions the strategies to overcome them. Thus, in a nutshell, this review will assist in understanding how CPPs can present novel possibilities for resolving the conventional issues faced with the present-day nanotherapeutics.

Who can earn risk-free profit? : Possibility of Arbitrage in the Hungarian Student Loan System

People without tertiary educational attainment are more affected by poverty. Thus, obtaining a higher degree of education can act as a key to pulling sections of society out of the poverty trap. In higher education, Hungary has a dual-track tuition policy, which offers restricted merit-based entry to state-funded universities, leading to entirely free higher education for a limited number of students. As the most disadvantaged students perform worse at secondary school, their chances of being enrolled in free tertiary education are much lower. To improve equity, students have access to a well-designed student loan system in Hungary. This study demonstrates that Hungary’s higher education funding policy is currently further widening the gap between the rich and the poor, as holding a Student Loan 1 and a Hungarian Government Security Plus (MÁP Plusz) position results in arbitrage for those who do not need to borrow to finance their tuition fee and living expenses during the academic years. Instead of supporting the catchingup process for students coming from low-income backgrounds, the Hungarian system provides additional financial aid to advantaged students. Based on an international comparison of student loan schemes, adopting a targeted approach instead of a universal one might be worthy of consideration, e.g. providing an interest rate subsidy to disadvantaged students or setting a lower income level of the student’s household as an eligibility criterion for borrowing.

Walking through the wonder years of artificial DNA: peptide nucleic acid

Peptide Nucleic Acid (PNA) serves as an artificial functional analog of DNA. Being immune to enzymatic degradation and possessing strong affinity towards DNA and RNA, it is an ideal candidate for many medical and biotechnological applications that are of antisense and antigene in nature. PNAs are anticipated to have its application in DNA and RNA detection as well as quantification, to serve as antibacterial and antiviral agents, and silencing gene for developing anticancer strategies. Although, their restricted entry in both eukaryotic and prokaryotic cells limit their applications. In addition, aggregation of PNA in storage containers reduces the quality and quantity of functional PNA that makes it inadequate for their mass production and storage. To overcome these limitations, researchers have modified PNA either by the addition of diverse functional groups at various loci on its backbone, or by synthesizing chimeras with other moieties associated with various delivery agents that aids their entry into the cell. Here, this review article summarizes few of the structural modifications that are performed with PNA, methods used to improve their cellular uptake and shedding light on the applications of PNA in various prospects in biological sciences.

ML-SA1, a selective TRPML agonist, inhibits DENV2 and ZIKV by promoting lysosomal acidification and protease activity

Arboviruses, especially Dengue virus (DENV) and Zika virus (ZIKV), have been a severe threat to human health in the last few years due to uncontrollable transmission. There are no approved vaccines or clinical drugs available for use to prevent and treat their infections. Transient receptor potential mucolipin 2 and 3 (TRPML2 and TRPML3) were reported to modulate viral entry, but the antiviral function of these modulators was unknown. Here, we reported that ML-SA1, a TRPML agonist, inhibited DENV2 and ZIKV in vitro in a dose-dependent manner. Time-of-drug-addition experiments showed that ML-SA1 mainly restricted viral entry. Moreover, the selective TRPML3 activator SN-2 was found to share a similar antiviral effect against DENV2 and ZIKV, but the specific TRPML1 agonist MK6-83 was not effective. Although ML-SA1 was further revealed to induce autophagy, its antiviral role was independent of autophagy induction. Finally, ML-SA1 was found to inhibit DENV2 and ZIKV by promoting lysosome acidification and protease activity to cause viral degradation. Together, our study identifies two TRPML agonists, ML-SA1 and SN-2, as potent inhibitors of DENV2 and ZIKV, which may lead to the discovery of new candidates against viruses.

Recruitment, retention, and adherence in a clinical trial: The Pediatric Heart Network's Marfan Trial experience.

The Pediatric Heart Network Marfan Trial was a randomized trial comparing atenolol versus losartan on aortic root dilation in 608 children and young adults with Marfan syndrome. Barriers to enrollment included a limited pool of eligible participants, restrictive entry criteria, and a diverse age range that required pediatric and adult expertise. Retention was complicated by a 3-year commitment to a complex study and medication regimen. The Network partnered with the Marfan Foundation, bridging the community with the research. The aims of this study are to report protocol and medication adherence and associated predictive factors, and to describe recruitment and retention strategies. Recruitment, retention, and adherence to protocol activities related to the primary outcome were measured. Retention was measured by percentage of enrolled participants with 3-year outcome data. Protocol adherence was calculated by completion rates of study visits, ambulatory electrocardiography (Holter monitoring), and quarterly calls. Medication adherence was assessed by the number of tablets or the amount of liquid in bottles returned. Centers were ranked according to adherence (high, medium, and low tertiles). Recruitment, retention, and adherence questionnaires were completed by sites. Descriptive statistics summarized recruitment, retention, and adherence, as well as questionnaire results. Regression modeling assessed predictors of adherence. Completion rates for visits, Holter monitors, and quarterly calls were 99%, 94%, and 96%, respectively. Primary outcome data at 3 years were obtained for 88% of participants. The mean percentage of medication taken was estimated at 89%. Site and age were associated with all measures of adherence. Young adult and African American participants had lower levels of adherence. Higher adherence sites employed more strategies; had more staffing resources, less key staff turnover, and more collaboration with referring providers; utilized the Foundation's resources; and used a greater number of strategies to recruit, retain, and promote protocol and medication adherence. Overall adherence was excellent for this trial conducted within a National Institutes of Health-funded clinical trial network. Strategies specifically targeted to young adults and African Americans may have been beneficial. Many strategies employed by higher adherence sites are ones that any site could easily use, such as greeting families at non-study hospital visits, asking for family feedback, providing calendars for tracking schedules, and recommending apps for medication reminders. Additional key learnings include adherence differences by age, race, and site, the value of collaborative learning, and the importance of partnerships with patient advocacy groups. These lessons could shape recruitment, retention, and adherence to improve the quality of future complex trials involving rare conditions.

Market Power and Patent Strategies: Evidence from Renaissance Venice

This paper exploits the introduction of the first regularized patent system, which appeared in the Venetian Republic in 1474, to examine the factors shaping inventors’ propensity to use a new form of intellectual property. We combine detailed information on craft guilds and patents in Renaissance Venice and show a negative association between patenting activity and guild statutory norms that strongly restricted entry and price competition. Our analysis shows that the heterogeneity in patenting activity documented by the industrial organization literature is not a special feature of modern technologies, but is rather a persistent phenomenon affected by market power.

COVID-19 in the West Indies: Trinidad and Tobago Experience

Trinidad and Tobago (T+T) is a small twin-island state in the Caribbean, eight miles off the coast of Venezuela. It has an area of approximately 5431 square kilometres and population of 1.4 million. At the present time, there are 116 coronavirus disease (COVID-19) cases and eight deaths, with no new cases or deaths for the last 21 days (May 17, 2020). Its COVID-19 story is one of the prompts, with early control and great success. There has beenno such instance where the health services were stretched or unable to cope. Even before the first case was identified, the T+T Government restricted entry to travelers from China, Japan, Singapore, South Korea and several European countries.The first case of COVID-19 identified in T+T was on March 12, 2020. The patient had returned from Switzerland. The next day, a second positive case was a person who had returned from USA.

A global treatments for coronaviruses including COVID-19.

In late December 2019 in Wuhan, China, several patients with viral pneumonia were identified as 2019 novel coronavirus (2019‐nCoV). So far, there are no specific treatments for patients with coronavirus disease‐19 (COVID‐19), and the treatments available today are based on previous experience with similar viruses such as severe acute respiratory syndrome‐related coronavirus (SARS‐CoV), Middle East respiratory syndrome coronavirus (MERS‐CoV), and Influenza virus. In this article, we have tried to reach a therapeutic window of drugs available to patients with COVID‐19. Cathepsin L is required for entry of the 2019‐nCoV virus into the cell as target teicoplanin inhibits virus replication. Angiotensin‐converting‐enzyme 2 (ACE2) in soluble form as a recombinant protein can prevent the spread of coronavirus by restricting binding and entry. In patients with COVID‐19, hydroxychloroquine decreases the inflammatory response and cytokine storm, but overdose causes toxicity and mortality. Neuraminidase inhibitors such as oseltamivir, peramivir, and zanamivir are invalid for 2019‐nCoV and are not recommended for treatment but protease inhibitors such as lopinavir/ritonavir (LPV/r) inhibit the progression of MERS‐CoV disease and can be useful for patients of COVID‐19 and, in combination with Arbidol, has a direct antiviral effect on early replication of SARS‐CoV. Ribavirin reduces hemoglobin concentrations in respiratory patients, and remdesivir improves respiratory symptoms. Use of ribavirin in combination with LPV/r in patients with SARS‐CoV reduces acute respiratory distress syndrome and mortality, which has a significant protective effect with the addition of corticosteroids. Favipiravir increases clinical recovery and reduces respiratory problems and has a stronger antiviral effect than LPV/r. currently, appropriate treatment for patients with COVID‐19 is an ACE2 inhibitor and a clinical problem reducing agent such as favipiravir in addition to hydroxychloroquine and corticosteroids.

Problems of Fact, Method, Theory, and Concepts in Tsoukas (2018)

On January, 27, 2017, U.S. President Donald J. Trump issued Executive Order 13769 on immigration and travel (EO 13769), which restricted entry into the U.S. of the citizens of seven primarily Muslim countries. Many academics reacted with outrage, including me and other members of the Academy of Management (AOM), of which I was President at the time. Some scholarly associations condemned EO 13769 as immoral, but the AOM did not immediately issue such a condemnation because the AOM’s Constitution included a policy of no-political-stands (NPSP) and a principle that nobody, including the AOM President, could represent personal views as those of the organization. Within a few weeks, the AOM Constitution was changed, and in October, 2017, the AOM joined other associations in issuing a condemnation. An article was published in this journal on this situation (Tsoukas in J Bus Ethics, https://doi.org/10.1007/s10551-018-3979-y, 2018) that was subsequently amended through a published Correction (Tsoukas in J Bus Ethics, https://doi.org/10.1007/s10551-019-04194-9, 2019), but the Correction only partially addressed the problems in the original. The main contribution of this commentary is to take up the invitation in Tsoukas (2018) to examine the case for insights on theoretical and conceptual questions raised in the literature on prototypicality and moral imagination. It also briefly outlines the most significant omitted errors of fact in Tsoukas (2018) that were not corrected in Tsoukas (2019), and describes the most important methodological problems in Tsoukas (2018). The conclusion suggests that the complex, nuanced, and evolving interactions that unfolded at the AOM are not fully addressed theoretically or conceptually in this literature.

Impact of COVID-19 outbreak in blood transfusion services in India: Experience from tertiary care blood centres in Kerala: A short review

Blood Transfusion Service (BTS) in India faced numerous challenges during the COVID-19 outbreak and the following imposed country lockdown. We aim to identify the challenges faced by selected blood centers and explore the mitigation strategies implemented during the COVID 19 pandemic and subsequent lockdown. Diminished donor inflow, lack of uniform donor selection criteria during the initial period, fear of COVID-19 spread to blood donors and staff personnel, shortage of available blood units, staff personnel transportation, handling of medical records, and concerns about transfusion-transmitted COVID-19 were the major challenges faced in our blood centers. Personal invitation of donors, public announcements, and in-house donation drives were implemented to improve donor inflow. Institute level donor selection protocol was developed and followed before the national guidelines were established. Restricted donor entry, stringent donor selection, and adequate sanitization strategies were the key steps adopted to ensure the safety of donors and staffs. In the interim, there was a reduction in blood unit requirement due to reduced patient inflow. Staff duty pattern was allocated on a rotation basis. The novel standard operating procedure was developed and implemented for handling COVID-19 positive or suspected blood samples. BTS should always be vigilant to adopt new practices even before guidelines are set by regulatory authorities and are liable to follow the guidelines. Restrictive blood transfusion strategies need to be emphasized in the country.

Synthesis of hydrophobically modified guar gum film for packaging materials

Guar gum was hydrophobically modified by microwave assisted condensation with dimer acid (DA, a dimer of ricinoleic acid derived from castor oil) under “green” conditions. The condensation product (HMG) was then blended with polyvinyl alcohol and cast into films abbreviated as HMGF (hydrophobically modified guar gum film). FTIR and UV–visible spectroscopies, X-ray diffractometry, swelling, permeability and tensile strength measurements were used to evaluate the properties of HMG and HMGF. HMGF exhibits optimal mechanical strength with UV protective effect and restricted entry of chemical contaminants. HMGF could be easily disposed by burying in soil. HMGF may be a potential eco-friendly food packaging material.

Understanding Germany’s response to the 2015 refugee crisis

Purpose This paper aims to understand the discrepancy between Germany’s immediate positive response to the so-called “Europe 2015's refugee crisis“ and the strict asylum legislation adopted in Germany in the following year. Design/methodology/approach The discrepancy is attributed to external and internal forces. The external force is Germany’s obligation to adhere to the Common European Asylum System. The internal force is the role of the different policy actors. The paper focuses on the role of the media as an example of a private policy actor. Through adopting the theory of the social construction of target populations, the paper studies how the media constructs “asylum seekers”, the target of the new asylum legislation. The role of the media is analyzed using the methodology of qualitative content analysis of a selected number of newspaper articles. Findings The majority of the studied articles problematized receiving and hosting refugees and focused on the reason behind migration differentiating between asylum seekers fleeing conflict areas and all others who might be abusing the asylum channel. The findings of the content analysis, as such, resonate with the amendments that focused on facilitating the integration of accepted “refugees” but restricted further entry. As such, it could be argued that these findings explain the influence of the media on the amendments and as such provide an explanation to the discrepancy between the initial response and the amendments. Research limitations/implications The analysis focused on one newspaper. The findings, as such, are not representative. The aim is only to provide an example of how the German media dealt with the refugee crisis and to suggest using the theory chosen by the paper to analyze the link between asylum legislation and the construction of asylum seekers. To understand how asylum legislation is influenced by how asylum seekers are constructed, more studies are needed. Such studies could analyze the role played by other media outputs and/or the role played by other policy actors in constructing the target of the policy. Originality/value The media’s response is based on analyzing a sample of newspaper articles published by a German newspaper following the so-called 2015 refugee crisis. Accordingly, the findings represent an original endeavor to understand how the media reacted to the crisis.

Improved covering arrays using covering perfect hash families with groups of restricted entries

Covering perfect hash families (CPHFs) are used to represent compactly some covering arrays. For CPHFs there is an efficient way to determine if the covering arrays derived from them are or not complete covering arrays; and this characteristic eases the construction of large covering arrays by greedy and metaheuristic methods working over the CPHF representation. CPHFs has been constructed in other works by backtracking, tabu search, simulated annealing, and greedy methods. The present work introduces a new simulated annealing algorithm that is able to construct CPHFs with groups of rows with restricted entries. In a CPHF of this kind the entries have some dependencies among them, that is, the values in some rows restrict the values that can appear in other rows. Restricted CPHFs produce covering arrays smaller than the ones derived from CPHFs without restricted entries. By using the new simulated annealing algorithm, we construct 135 new CPHFs whose derived covering arrays improve the upper bound of 19,669 covering array numbers.

Liposomal Formulations for Nose-to-Brain Delivery: Recent Advances and Future Perspectives.

Restricted drug entry to the brain that is closely associated with the existence of the blood brain barrier (BBB) has limited the accessibility of most potential active therapeutic compounds to the brain from the systemic circulation. Recently, evidences for the presence of direct nose-to-brain drug transport pathways have been accumulated by several studies and an intranasal drug administration route has gained attention as a promising way for providing direct access to the brain without the needs to cross to the BBB. Studies aiming for developing nanoparticles as an intranasal drug carrier have shown considerable promise in overcoming the challenges of intranasal drug delivery route. This review gives a comprehensive overview of works having investigated liposomes as a potential vehicle to deliver drugs to the brain through nose-to-brain route while considering the excellent biocompatibility and high potential of liposomes for clinical development. Herein, studies are reviewed with special emphasis on the impact of formulation factors, such as liposome composition and surface modification of liposomes with targeting moieties, in addition to intranasal environmental factors that may affect the extent/site of absorption of intranasally administered, liposome-encapsulated drugs.

Hypoxic Non-replicating Persistent Mycobacterium tuberculosis Develops Thickened Outer Layer That Helps in Restricting Rifampicin Entry.

Bacteria undergo adaptive morphological changes to survive under stress conditions. The present work documents the morphological changes in Mycobacterium tuberculosis (Mtb) cells cultured under hypoxic condition using Wayne’s in vitro hypoxia model involving non-replicating persistence stages 1 and 2 (NRP stage 1 and NRP stage 2) and reveals their physiological significance. Transmission electron microscopy of the NRP stage 2 cells showed uneven but thick outer layer (TOL), unlike the evenly thin outer layer of the actively growing mid-log phase (MLP) cells. On the contrary, the saprophytic Mycobacterium smegmatis NRP stage 2 cells lacked TOL. Scanning electron microscopy (SEM) and atomic force microscopy (AFM) of the Mtb NRP stage 2 cells confirmed the rough uneven surface unlike the smooth surface of the MLP cells. Zeta potential measurements showed high negative charge on the surface of NRP stage 2 cells and polysaccharide specific calcofluor white (CFW) staining of the cells revealed high content of polysaccharide in the TOL. This observation was supported by the real-time PCR data showing high levels of expression of the genes involved in the synthesis of sugars, such as trehalose, mannose and others, which are implicated in polysaccharide synthesis. Experiments to understand the physiological significance of the TOL revealed restricted entry of the biologically low-active 5-carboxyfluorescein-rifampicin (5-FAM-RIF), at concentrations equivalent to microbicidal concentrations of the unconjugated biologically active rifampicin, into the NRP stage 2 cells, unlike in the MLP cells. Further, as expected, mechanical removal of the TOL by mild bead beating or release of the NRP stage 2 cells from hypoxia into normoxia in fresh growth medium also significantly increased 5-FAM-RIF permeability into the NRP stage 2 cells to an extent comparable to that into the MLP cells. Taken together, these observations revealed that Mtb cells under hypoxia develop TOL that helps in restricting rifampicin entry, thereby conferring rifampicin tolerance.

Improving the innovation ability of engineering students: a Science and Technology Innovation Community organisation network analysis

ABSTRACT Science and Technology Innovation Communities (STICs) are student-led partnerships that bring together businesses, research centres, and university staff. They constitute an effective way of promoting student innovation ability. However, the students’ position within the STICs organisation network may condition how their innovation ability is effectively acquired. Using Social Network Analysis (SNA), this study measures how the STICs organisation network promotes the innovation ability of its actors. The paper finds that network centrality and structural holes of the STICs organisation network are positively correlated with student innovation ability. The results are validated through robustness tests in three different STICs, involving engineering students from China’s Chang’an University. Semi-structured interviews are also conducted with 20 relevant actors of STICs. The conclusion suggests that a higher involvement of core actors, more support from schools, and more restrictive entry requirements are necessary to improve the organisation management and training level of engineering students in STICs.

On the determinants and permanents of matrices with restricted entries over prime fields

Let $A$ be a set in a prime field $\mathbb{F}_p$. In this paper, we prove that $d\times d$ matrices with entries in $A$ determine almost $|A|^{3+\frac{1}{45}}$ distinct determinants and almost $|A|^{2-\frac{1}{6}}$ distinct permanents when $|A|$ is small enough.

English

Inflow-control devices (ICDs) were developed to avoid coning problems in long horizontal wells mainly in heterogenous formations, but cause some additional drawdown which does not contribute to rate increase. This rate reduction is seen to be impairment to the productivity of horizontal wells. Therefore, horizontal wells that are equipped with ICDs require a pre-quantification of their productivity by determining skin caused by each ICD nozzle size. This will help prevent additional expenditure that will be spent for a corrective horizontal well intervention. Many authors have proposed equations that can be used to estimate skin due to damage, partial completion, slanted well and perforation. No author has provided a skin equation that can be used to estimate recoverable and productivity loss that may result from the use of inflow control devices. In this work, a 3D numerical model which includes inflow control devices along horizontal wells was used to investigate reservoir and production performances of various ICD nozzle sizes. Different productivity losses from different nozzle sizes were seen as skin and a 0.002ft2 ICD nozzle flow area estimated to have a zero skin. Consequently, a simple equation for calculating this skin due to restricted fluid entry through ICD nozzles was derived. The derived equation which shows insignificant deviation from skin equation is then used for selecting the right nozzle size for production and recovery optimization from horizontal wells. Key words: Inflow control device