Free self-assembly of spontaneously chiral, supramolecular structures

In this thesis, Molecular Dynamics simulations are used to investigate the free selfassembly of supramolecular, chiral structures. The main coarse-grained model used for this is the disc-shaped variant of the Gay-Berne potential. This is parameterised to favour face-face configurations, consistent with chromonic molecules which tend to stack due to their π − π interactions. Additionally, assemblies formed by mixtures of these discs and a second species, modelled as Lennard-Jones spheres, are investigated. Here, hot-spot zones on the rims of the discs are used to provide strong interactions with the spheres. Simulations of disc-only systems lead to self-assembly of multi-thread, chiral fibres. Depending on the choice of particle shape and face-face interaction strength, the formed fibres are reproducibly either straight or, for reasons of packing efficiency, spontaneously chiral. As they grow radially, increasing stresses cause chiral fibres to untwist either continuously or via morphological rearrangement. It is also found that, due to the kinetics of fibre initiation, the isotropic solution has to be significantly supercooled before aggregation takes place. As a result, the thermal hysteresis of the formed fibres extends to 10-20% of their formation temperatures. The kinetic barriers to the early stages of growth are investigated by the introduction of a small permanent seed. Depending on the size of the seed, monotonic fibre growth is then observed 5-10% above the normal formation temperatures. On introducing Lennard-Jones spheres and hot-spot zones at the rims of discs, twisted bilayer ribbons, sandwiching a helicoidal sphere layer, are obtained. Systematic investigation of the effects of hot-spot size on the formation and structural properties of these twisted bilayers is then performed. This shows that lateral growth of these bilayers, and the associated increases in bend stresses, lead to the development of defect lines. For relatively small hot-spot sizes, rope structures with five helical threads of discs wrapped around a sphere core self-assemble. Where such ropes aggregate, geometrical frustration leads to multi-rope structures undergoing morphological rearrangement into double-bilayers. Extending the model by giving the discs double hot-spots leads to the formation of a multi-layer twisted bundle with three different directions of growth and three modes of twist. If the sizes of the interacting particles are changed, then, further new arrangements result. For thinner discs, a different class of bilayer is found in which the threads in the two leaflets are mutually orthogonal. This is shown to provide a new pathway for formation of tubes by a rolling-up mechanism involving intermediate saddle bilayer and half-pipe structures. The dimensions of such tubes are found to be very sensitive to the extent of the hot-spot. Double-helix structures, involving two helices of discs wrapped around a central thread of sphere, are the other major class of supramolecular assembly adopted by systems involving thinner discs. Finally, the interaction of self-assembled objects, leading to behaviours such as the formation of multi-bilayer structures, is shown to be accessed on the time- and length-scales of this class of computer simulation

Free self-assembly of spontaneously chiral, supramolecular structures

In this thesis, Molecular Dynamics simulations are used to investigate the free selfassembly of supramolecular, chiral structures. The main coarse-grained model used for this is the disc-shaped variant of the Gay-Berne potential. This is parameterised to favour face-face configurations, consistent with chromonic molecules which tend to stack due to their π − π interactions. Additionally, assemblies formed by mixtures of these discs and a second species, modelled as Lennard-Jones spheres, are investigated. Here, hot-spot zones on the rims of the discs are used to provide strong interactions with the spheres. Simulations of disc-only systems lead to self-assembly of multi-thread, chiral fibres. Depending on the choice of particle shape and face-face interaction strength, the formed fibres are reproducibly either straight or, for reasons of packing efficiency, spontaneously chiral. As they grow radially, increasing stresses cause chiral fibres to untwist either continuously or via morphological rearrangement. It is also found that, due to the kinetics of fibre initiation, the isotropic solution has to be significantly supercooled before aggregation takes place. As a result, the thermal hysteresis of the formed fibres extends to 10-20% of their formation temperatures. The kinetic barriers to the early stages of growth are investigated by the introduction of a small permanent seed. Depending on the size of the seed, monotonic fibre growth is then observed 5-10% above the normal formation temperatures. On introducing Lennard-Jones spheres and hot-spot zones at the rims of discs, twisted bilayer ribbons, sandwiching a helicoidal sphere layer, are obtained. Systematic investigation of the effects of hot-spot size on the formation and structural properties of these twisted bilayers is then performed. This shows that lateral growth of these bilayers, and the associated increases in bend stresses, lead to the development of defect lines. For relatively small hot-spot sizes, rope structures with five helical threads of discs wrapped around a sphere core self-assemble. Where such ropes aggregate, geometrical frustration leads to multi-rope structures undergoing morphological rearrangement into double-bilayers. Extending the model by giving the discs double hot-spots leads to the formation of a multi-layer twisted bundle with three different directions of growth and three modes of twist. If the sizes of the interacting particles are changed, then, further new arrangements result. For thinner discs, a different class of bilayer is found in which the threads in the two leaflets are mutually orthogonal. This is shown to provide a new pathway for formation of tubes by a rolling-up mechanism involving intermediate saddle bilayer and half-pipe structures. The dimensions of such tubes are found to be very sensitive to the extent of the hot-spot. Double-helix structures, involving two helices of discs wrapped around a central thread of sphere, are the other major class of supramolecular assembly adopted by systems involving thinner discs. Finally, the interaction of self-assembled objects, leading to behaviours such as the formation of multi-bilayer structures, is shown to be accessed on the time- and length-scales of this class of computer simulation

Potential effect of coenzyme Q10 (Ubiquinone) on serum NGAL biomarker and kidney function following Coronary Artery Bypass Grafting surgery

Background: Acute kidney injury (AKI) is a common complication after coronary artery bypass grafting (CABG) surgery, and is associated with major adverse outcomes. Effect of preoperative administration of coenzyme Q10 was evaluated in order to realize that whether it could prevent the occurrence of AKI following elective CABG surgery. Materials and Methods: Two hundred and fifty patients who were candidate for elective CABG surgery between September 2017 and August 2018 were randomly assigned to intervention group (receiving coenzyme Q10, 300 mg BID for 2 days before surgery) and control group. Serum NGAL (neutrophil gelatinase-associated lipocalin) was measured at baseline, 6 and 24 hours after surgery. Serum creatinine (sCr) and urine output (UO) were also measured at baseline and after surgery. Results: Fifty patients completed the study. The total incidence of acute kidney injury was 32%. There were no significant differences in the incidence of AKI (p=0.07) between the two groups. Serum NGAL was shown no significant difference at 6 (p=0.13) and 24 (p=0.22) hours after surgery compared to the baseline level between the two groups, whereas, the significant difference in the hospitalization duration was shown between them (p=0.02). Conclusion: CoQ10 supplementation did not significantly decrease the incidence of AKI in patients undergoing elective CABG

Evaluating the Effects of Umifenovir Compared to Lopinavir/Ritonavir in the Management of Patients with COVID-19: A Randomized Controlled Trial

Background. Due to the lack of specific safe medications for the treatment of COVID-19, medications used for other similar conditions are being tested to alleviate the condition of COVID-19 patients, resulting in acceptable outcomes in some cases. Umifenovir (Arbidol®) is used to treat influenza viruses by inhibiting the fusion of the virus with the host cell. According to previous findings, umifenovir may inhibit SARS-CoV-2 infection by interfering with the release of SARS-CoV-2 from inside the cell. This study aimed to determine the effects of umifenovir, a fusion inhibitor, versus lopinavir/ritonavir in treating patients with COVID-19. Methods. This study was a randomized controlled trial consisting of 90 confirmed COVID-19 patients divided into the lopinavir/ritonavir group and the umifenovir group. The lopinavir/ritonavir group received 100/25 mg twice, while the umifenovir group was given 200 mg thrice a day, in both groups, for seven days. Outcomes included mortality rate and the need for mechanical ventilation or intensive care unit admission. Length of stay in the hospital and ICU and the lab tests trend were also assessed. Results. The mortality rate and the need for admission to the ICU were significantly lower in the umifenovir group (8% vs. 27.5%; P-value = 0.02). Moreover, The levels of white blood cells were also lower in the umifenovir group than in the control group by day 10 (6.2 (5.3-7.4) vs. 10.8 (9.9-13); P-value <0.001). Conclusions. Umifenovir may reduce the need for admission to the ICU and mortality rate in patients with COVID-19 compared with lopinavir/ritonavir. The lab test trends were also in favor of umifenovir use.

Self-assembly of twisted, multi-sheet aggregates

Hierarchical self-assembly underpins much of the diversity of form and function seen in soft systems, yet the pathways by which they achieve their final form are not always straightforward – intermediate steps, kinetic effects and finite sizes of aggregates all influence the self-assembly pathways of these systems. In this paper, we use molecular dynamics simulations of binary mixtures of spheres and ellipsoidal discs to investigate the self-assembly of anisotropic aggregates with internal structures. Through this, the full aggregation pathways of spontaneously chiral, multi-bilayer and multi-layer assemblies have been tracked and characterised via a semi-qualitative analysis. This includes the unambiguous identification of first-, second- and third-generation hierarchical assemblies within a single simulation. Given the significant challenge of tracking full aggregation pathways in experimental systems, our findings strongly support the notion that molecular simulation has much to contribute to improving our understanding of hierarchical self-assembling systems

Effect of L-Carnitine on Troponin, IL6 and HS– CRP levels after Coronary Artery Bypass Graft Surgery

Background: L-carnitine seems to be able to prevent complications after heart surgery using Cardiopulmonary bypass (CPB) and the adverse effects of pump usage. This study aimed to evaluates the effects of L-carnitine on cardiac biomarkers and operation characteristics after coronary artery bypass graft (CABG) surgery.Methods and materials: In this randomized triple-blinded, sixty patients undergoing elective CABG surgery were divided into three equal groups to receive 2gr oral L-carnitine (group A), 5gr oral L-carnitine (group B) and placebo (group C) 2 hours before surgery. IL-6, creatinine, and high sensitivity C-reactive protein (HS–CRP) levels, CK-MB, cardiac troponin and inotrope administration in ICU or after CPB were recorded for all patients at baseline levels and at 8 or 24 hours postoperatively.Results: There was an evidence of a significant difference in CPK-MB level and number of red blood cell packed used in group A was lower than group C (p<0.05). The cardiac troponin level 8 hours after surgery significantly decreased in two treatment groups in comparison to group C (p<0.05). The need for inotropic support after weaning from CPB, in B group was statistically higher than C group (p=0.021).Conclusion: Although L-carnitine adjunct therapy appears not to be associated with IL-6 and HS–CRP levels, it had beneficial effects on cardiac troponin and CPK-MB levels.   Keywords: Coronary artery bypass graft surgery, IL-6, HS–CRP levels, L-carnitine, Troponi

Thermal hysteresis and seeding of twisted fibers formed by achiral discotic particles

In this paper, molecular dynamics simulations of simple disc-shaped particles are used to investigate the free self-assembly of defect-free fibers. Depending on the choice of particle shape and interaction strength, the formed fibers are reproducibly either straight or, for reasons of packing efficiency, spontaneously chiral. As they grow radially, increasing stresses cause chiral fibers to untwist either continuously or via morphological rearrangement. It is also found that, due to the kinetics of fiber initiation, the isotropic solution has to be significantly supercooled before aggregation takes place. As a result, the thermal hysteresis of one formed fiber extends to 13.9% of the formation temperature. In the presence of a three-thread seed cluster of 15 particles, however, monotonic fiber growth is observed 9.3% above the normal formation temperature. Thus, as in many experimental systems, it is the kinetic pathway, rather than the thermodynamic stability of the final assembly, that dominates the observed behavior

Carvacrol exerts nephroprotective effect in rat model of diclofenac-induced renal injury through regulation of oxidative stress and suppression of inflammatory response

Diclofenac (DIC) is an NSAID that can cause toxic effects in animals and humans and carvacrol (CAR) is a monoterpene compound that displays effective pharmacological and biological actions. The purpose of this work was to assess the influences of CAR on DIC-induced renal injury and oxidative stress in male rats. The rats were segregated into four groups. Group 1, control group; Group 2 received DIC-only; Groups 3, received CAR-only and group 4 received DIC plus CAR. Changes in biochemical indexes, pathological changes, molecular biological indexes, and genes related to the inflammation of main organs were evaluated. The results of this work indicated that the amounts of the serum protein carbonyl, sGOT, sGPT, urea, creatinine, uric acid, nitrite content, MDA, serum TNF-alpha, and renal TNF-alpha gene expression were remarkably increased and the levels of the GPx, GSH, CAT, and SOD were significantly reduced in DIC-only treated animals compared to the control group. On the other hand, treatment with CAR after exposure to DIC led to significant improvements in abnormalities of DIC-induced renal injury and serum biochemical factors. The data approve that CAR diminished the deleterious effects of DIC exposure. In this regard, the findings of this study indicated that the administration of CAR could alleviate the noxious effects of DIC on the antioxidant defense system and renal tissue

"Familial" versus "Sporadic" intellectual disability: contribution of common microdeletion and microduplication syndromes

<p>Abstract</p> <p>Background</p> <p>Interstitial Microdeletion and Microduplication syndromes have been proposed as a significant cause of sporadic intellectual disability (ID) but the role of such aberrations in familial ID has not yet been investigated. As the balanced chromosomal abnormalities commonly lead to the recurrent ID or multiple congenital anomalies, this study was designed to evaluate whether it was justified to investigate such aberrations in familial ID patients. Three hundred and twenty eight patients from 101 unrelated Iranian families with more than two ID patients in the first-degree relatives, have been investigated. Assessment of a panel of 21 common Microdeletion and Microduplication syndromes (CMMS) was carried out using Multiplex Ligation-Dependent Probe Amplification (MLPA) technique.</p> <p>Results</p> <p>Among the families studied, 27.7% had 4-12, 35.6% had 3 and 36.6% had 2 affected individuals in the first-degree relatives. An autosomal dominant inheritance of Williams-Beuren syndrome (WBS) was detected in a family with no clinical suspicion of WBS. The prevalence of CMMS was therefore,0.99%.</p> <p>Conclusion</p> <p>This is the first investigation of a panel of CMMS in a large sample set of "familial ID patients". The findings of this study showed the low prevalence of CMMSs in "familial ID" patients in spite of the significant contribution of such aberrations in "sporadic ID" which has a very useful practical impact by avoiding unnecessary diagnostic tests in "familial ID" patients.</p

Video2:FibreUntwisting

In this video, the initiation and growth of a fibre in a system with κ = 0.345, κ′ = 0.15 and 20,000 discs at T=1.57, discussed in Section 4.5, is shown. In this system, a multi-step untwisting process was observed and the final fibre was straight.<br>For visualization, a plane at the centre of the straight fibre at the step of 13 million was identified and different colours are assigned to each thread of particles in this plane. The particles being a part of the identified threads at the final configuration are drawn with their true colour in the course of self-assembly. Other particles in the cluster are shown by their short axes. This illustrates how the threads maintain<br>their integrity during the untwisting scenario