An investigation into approximate solutions for deterministic and stochastic multi-dimensional sequencing

A description is given of an investigation in detail into the validity of the overlap integral method for describing planar optical waveguide junctions. A comparison between the results of this method and that of a rigorous mode-matching approach is taken

Free energies of membrane stalk formation from a lipidomics perspective

Many biological membranes are asymmetric and exhibit complex lipid composition, comprising hundreds of distinct chemical species. Identifying the biological function and advantage of this complexity is a central goal of membrane biology. Here, we study how membrane complexity controls the energetics of the first steps of membrane fusions, that is, the formation of a stalk. We first present a computationally efficient method for simulating thermodynamically reversible pathways of stalk formation at coarse-grained resolution. The method reveals that the inner leaflet of a typical plasma membrane is far more fusogenic than the outer leaflet, which is likely an adaptation to evolutionary pressure. To rationalize these findings by the distinct lipid compositions, we computed ~200 free energies of stalk formation in membranes with different lipid head groups, tail lengths, tail unsaturations, and sterol content. In summary, the simulations reveal a drastic influence of the lipid composition on stalk formation and a comprehensive fusogenicity map of many biologically relevant lipid classes

Obstetric and neonatal outcome among women presenting with reduced fetal movements in third trimester

Background: Reduced maternal perception of fetal movements allows early identification, timely evaluation and intervention for fetuses at risk of adverse outcome. The primary objective of this study was to assess the pregnancy characteristics and outcomes of pregnant women presenting to hospital with reduced fetal movements (RFM).Methods: Prospective observational study, recruiting all women with singleton pregnancy at or beyond 28 weeks of gestation presenting with a subjective perception of RFM from April 2015 to December 2016. Maternal characteristics, antenatal risk factors, management pathways and perinatal outcome studied.Results: 47% belonged to high risk pregnancy. Among high risk women, although only 39% showed poor BPP at the first presentation, 58% were delivered irrespective of their gestational age, out of which 32.75% had poor neonatal outcome. Among low risk who had >2 episodes of RFM, 50% had poor neonatal outcome. 7% among high risk pregnancies and 18% among low risk, presented with RFM within 48 hours following steroid prophylaxis.24% of high risk women showed liquor volume abnormalities as compared to low risk (6.3%).Conclusions: Significant proportion of those with RFM belonged to high risk pregnancy. Among high risk group, there were high rates of stillbirth and poor BPP at the time of admission when compared to low risk group. Due to early approach to the hospital and timely intervention, significant women with abnormal BPP had good perinatal outcome. All those fetuses who were delivered on first episode of RFM in low risk group did not show evidence of compromise at birth, probably indicating unnecessary delivery. More than 2 episodes of RFM even among low risk group seems significant as good number of fetuses were compromised at birth. Steroids prophylaxis for the fetal lung maturity causes transient changes in BPP, hence unnecessary delivery should be avoided especially those among low risk pregnancy

Is Lipid Specificity Key to the Potential Antiviral Activity of Mouthwash Reagent Chlorhexidine against SARS-CoV-2?

Chlorhexidine (CHX), a popular antibacterial drug, is widely used for oral health. Emerging pieces of evidence suggest that commercially available chlorhexidine mouthwash formulations are effective in suppressing the spread of SARS-CoV-2, possibly through destabilization of the viral lipid envelope. CHX is known for its membrane-active properties; however, the molecular mechanism revealing how it damages the viral lipid envelope is yet to be understood. Here we used extensive conventional and umbrella sampling simulations to quantify the effects of CHX on model membranes mimicking the composition of the SARS-CoV-2 outer lipid membrane as well as the host plasma membrane. Our results show that the lipid composition and physical properties of the membrane play an important role in binding and insertion, with CHX binding favorably to the viral membrane over the plasma membrane. Among the simulated lipids, CHX preferentially binds to anionic lipids, PS and PI, which are more concentrated in the viral membrane. The deeper and stable binding of CHX to the viral membrane results in more pronounced swelling of the membrane laterally with a thinning of the bilayer. The overall free energies of pore formation are strongly reduced for the viral membrane compared to the plasma membrane; however, CHX has a larger concentration-dependent effect on free energies of pore formation in the plasma membrane than the viral membrane. The results indicate that CHX is less toxic to the human plasma membrane at low concentrations. Our simulations reveal that CHX facilitates pore formation by the combination of thinning the membrane and accumulation at the water defect. This study provides insights into the mechanism underlying the anti-SARS-CoV-2 potency of CHX, supporting its potential for application as an effective and safe oral rinse agent for preventing viral transmission

Cooperative Effects of an Antifungal Moiety and DMSO on Pore Formation over Lipid Membranes Revealed by Free Energy Calculations

Itraconazole is a triazole drug widely used in the treatment of fungal infections, and it is in clinical trials for treatment of several cancers. However, the drug suffers from poor solubility, while experiments have shown that itraconazole delivery in liposome nanocarriers improves both circulation half-life and tissue distribution. The drug release mechanism from the nanocarrier is still unknown, and it depends on several factors including membrane stability against defect formation. In this work, we used molecular dynamics simulations and potential of mean force (PMF) calculations to quantify the influence of itraconazole on pore formation over lipid membranes, and we compared the effect by itraconazole with a pore-stabilizing effect by the organic solvent dimethyl sulfoxide (DMSO). According to the PMFs, both itraconazole and DMSO greatly reduce the free energy of pore formation, by up to similar to 20 kJ mol(-1). However, whereas large concentrations of itraconazole of 8 mol % (relative to lipid) were required, only small concentrations of a few mole % DMSO (relative to water) were sufficient to stabilize pores. In addition, itraconazole and DMSO facilitate pore formation by different mechanisms. Whereas itraconazole predominantly aids the formation of a partial defect with a locally thinned membrane, DMSO mainly stabilizes a transmembrane water needle by shielding it from the hydrophobic core. Notably, the two distinct mechanisms act cooperatively upon adding both itraconazole and DMSO to the membrane, as revealed by an additional reduction of the pore free energy. Overall, our simulations reveal molecular mechanisms and free energies of membrane pore formation by small molecules. We suggest that the stabilization of a locally thinned membrane as well as the shielding of a transmembrane water needle from the hydrophobic membrane core may be a general mechanism by which amphiphilic molecules facilitate pore formation over lipid membranes at sufficient concentrations.Peer reviewe

Incarcerated foreign body in the vagina of a postmenopausal lady

Vaginal foreign bodies retained for long duration are uncommon in present day scenario. When a female presents with recurrent foul smelling vaginal discharge, foreign body should be suspected. Here is a report of foreign body in the vagina of a postmenopausal lady

Ion-induced transient potential fluctuations facilitate pore formation and cation transport through lipid membranes

Unassisted ion transport through lipid membranes plays a crucial role in many cell functions without which life would not be possible, yet the precise mechanism behind the process remains unknown due to its molecular complexity. Here, we demonstrate a direct link between membrane potential fluctuations and divalent ion transport. High-throughput wide-field second harmonic (SH) microscopy shows that membrane potential fluctuations are universally found in lipid bilayer systems. Molecular dynamics simulations reveal that such variations in membrane potential reduce the free energy cost of transient pore formation and increase the ion flux across an open pore. These transient pores can act as conduits for ion transport, which we SH image for a series of divalent cations (Cu$^{2+}$, Ca$^{2+}$, Ba$^{2+}$, Mg$^{2+}$) passing through GUV membranes. Combining the experimental and computational results, we show that permeation through pores formed via an ion-induced electrostatic field is a viable mechanism for unassisted ion transport.Comment: 8 pages, 2 figure

Obstetric hysterectomy in a tertiary centre: a 3-year retrospective study

Background: Obstetric hysterectomy (OH) is a life-saving procedure and involves removal of uterus in cases of intractable hemorrhage. This study includes 21 cases of OH in a period of 3 years at a tertiary centre. We sought to understand the prevalence, indications and outcomes of emergency obstetric hysterectomy. Methods: This is a retrospective, observational study, conducted with the means of hospital delivery records in a tertiary care centre in Navi Mumbai. We included all patients who underwent obstetric hysterectomy in a span of 3 years between 1st April 2020 to 31st March 2023, in Dr. D.Y. Patil Hospital, Navi Mumbai, India. Results: Twenty- one OH were done in the period of study. The incidence of obstetric hysterectomy was 0.45% (452 OH per 100,000 deliveries). It was more prevalent in patients with caesarean section compared to vaginal delivery. Women between the age 25-35 years group comprised of 57.15% cases. Out of the 21 women in the study 7 women were primigravida (33.33%). Most common cause for OH was observed to be uterine atony (42.85%) followed by adherent placenta (28.57%). Maternal morbidity like admission to intensive care unit and need for blood and blood product transfusion was noted in most patients, mortality was observed in only 1 case. Neonatal mortality was nil in this study but, admission to neonatal intensive care unit was required in 7 patients. Conclusions: Although, obstetric hysterectomy kills the future reproductive prospect for a woman, it is life saving for her. Timely decision for OH can not only prevent mortality but, also morbidity for the woman. Previous caesarean section and multigravida have higher incidence of OH. Atonicity is the predominant cause for obstetric hysterectomy in this study

Lipid Droplets Embedded in a Model Cell Membrane Create a Phospholipid Diffusion Barrier

Lipid droplets (LDs) are ubiquitous, cytoplasmic fat storage organelles that originate from the endoplasmic reticulum (ER) membrane. They are composed of a core of neutral lipids surrounded by a phospholipid monolayer. Proteins embedded into this monolayer membrane adopt a monotopic topology and are crucial for regulated lipid storage and consumption. A key question is, which collective properties of protein-intrinsic and lipid-mediated features determine spatio-temporal protein partitioning between phospholipid bilayer and LD monolayer membranes. To address this question, a freestanding phospholipid bilayer with physiological lipidic composition is produced using microfluidics and micrometer-sized LDs are dispersed around the bilayer that spontaneously insert into the bilayer. Using confocal microscopy, the 3D geometry of the reconstituted LDs is determined with high spatial resolution. The micrometer-sized bilayer-embedded LDs present a characteristic lens shape that obeys predictions from equilibrium wetting theory. Fluorescence recovery after photobleaching measurements reveals the existence of a phospholipid diffusion barrier at the monolayer–bilayer interface. Coarse-grained molecular dynamics simulation reveals lipid specific density distributions along the pore rim, which may rationalize the diffusion barrier. The lipid diffusion barrier between the LD covering monolayer and the bilayer may be a key phenomenon influencing protein partitioning between the ER membrane and LDs in living cells

Enhanced EPR directed and Imaging guided Photothermal Therapy using Vitamin E Modified Toco-Photoxil

Herein we report synthesis, characterization and preclinical applications of a novel hybrid nanomaterial Toco-Photoxil developed using vitamin E modified gold coated poly (lactic-co-glycolic acid) nanoshells incorporating Pgp inhibitor d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) as a highly inert and disintegrable photothermal therapy (PTT) agent. Toco-Photoxil is highly biocompatible, physiologically stable PTT material with an average diameter of 130 nm that shows good passive accumulation (2.3% ID) in solid tumors when delivered systemically. In comparison to its surface modified counterparts such as IR780-Toco-Photoxil, FA-Toco-Photoxil or FA-IR780-Toco-Photoxil accumulation are merely ~0.3% ID, ~0.025% ID and ~0.005% ID in folate receptor (FR) negative and positive tumor model. Further, Toco-Photoxil variants are prepared by tuning the material absorbance either at 750 nm (narrow) or 915 nm (broad) to study optimal therapeutic efficacy in terms of peak broadness and nanomaterial’s concentration. Our findings suggest that Toco-Photoxil tuned at 750 nm absorbance is more efficient (P = 0.0097) in preclinical setting. Toco-Photoxil shows complete passiveness in critical biocompatibility test and reasonable body clearance. High tumor specific accumulation from systemic circulation, strong photothermal conversion and a very safe material property in body physiology makes Toco-Photoxil a superior and powerful PTT agent, which may pave its way for fast track clinical trial in future