Molecular mechanisms and energetics of lipid droplet formation and directional budding.

The formation and budding of lipid droplets (LDs) are known to be governed by the LD size and by membrane tensions in the endoplasmic reticulum (ER) bilayer and LD-monolayers. Using coarse-grained simulations of an LD model, we first show that ER-embedded LDs of different sizes can form through a continuous transition from wide LD lenses to spherical LDs at a fixed LD size. The ER tendency to relax its bilayer modulates the transition via a subtle interplay between the ER and LD lipid densities. By calculating the energetic landscape of the LD transition, we demonstrate that this size-independent transition is regulated by the mechanical force balance of ER and LD-tensions, independent from membrane bending and line tension whose energetic contributions are negligible according to our calculations. Our findings explain experimental observation of stable LDs of various shapes. We then propose a novel mechanism for directional LD budding where the required membrane asymmetry is provided by the exchange of lipids between the LD-monolayers. Remarkably, we demonstrate that this budding process is energetically neutral. Consequently, LD budding can proceed by a modest energy input from proteins or other driving agents. We obtain equal lipid densities and membrane tensions in LD-monolayers throughout budding. Our findings indicate that unlike LD formation, LD budding by inter-monolayer lipid exchange is a tension-independent process.

A Eukaryotic Sensor for Membrane Lipid Saturation.

Maintaining a fluid bilayer is essential for cell signaling and survival. Lipid saturation is a key factor determining lipid packing and membrane fluidity, and it must be tightly controlled to guarantee organelle function and identity. A dedicated eukaryotic mechanism of lipid saturation sensing, however, remains elusive. Here we show that Mga2, a transcription factor conserved among fungi, acts as a lipid-packing sensor in the ER membrane to control the production of unsaturated fatty acids. Systematic mutagenesis, molecular dynamics simulations, and electron paramagnetic resonance spectroscopy identify a pivotal role of the oligomeric transmembrane helix (TMH) of Mga2 for intra-membrane sensing, and they show that the lipid environment controls the proteolytic activation of Mga2 by stabilizing alternative rotational orientations of the TMH region. This work establishes a eukaryotic strategy of lipid saturation sensing that differs significantly from the analogous bacterial mechanism relying on hydrophobic thickness.

Generalized FDTD scheme for the simulation of electromagnetic scattering in moving structures.

Electromagnetic scattering in moving structures is a fundamental topic in physics and engineering. Yet no general numerical solution to related problems has been reported to date. We introduce here a generalized FDTD scheme to remedy this deficiency. That scheme is an extension of the FDTD standard Yee cell and stencil that includes not only the usual, physical fields but also auxiliary, unphysical fields allowing a straightforward application of moving boundary conditions. The proposed scheme is illustrated by four examples - a moving interface, a moving slab, a moving crystal and a moving gradient - with systematic validation against exact solutions.

Orthogonal analysis of space-time crystals.

This paper presents a space-time-wise orthogonal analysis of space-time crystals. This analysis provides a solution consisting of a pair of explicit parametric equations that result from a separate application of the Bloch-Floquet theorem in the (orthogonal) directions of space and time. Compared with previous approaches, this solution offers the benefits of greater simplicity, clearer emphasis on space-time duality, and deeper physical insight.

Vesicle constriction by rings of Janus nanoparticles and aggregates of curved proteins.

Membrane constriction and associated scission by proteins and nano structures are crucial to many processes in cellular and synthetic biology. We report mechanical constriction of vesicles by rings of adsorbed Janus nanoparticles that represent synthetic nano structures and mimic contractile proteins, and by aggregates of curved crescents that mimic scaffold proteins. Membrane energetics from Monte Carlo simulations and simulated annealing of the elastic membrane model confirms spontaneous vesicle constriction by aggregates of sufficiently-curved crescents of various lengths and by rings of Janus nanoparticles with a variety of ring lengths, particle sizes, and particle area fractions. We show that shorter rings of smaller particles with higher area fractions reinforce the constriction by increasing the energetic drive towards the constricted vesicle with smaller constriction radius. We demonstrate that vesicle constriction by crescent aggregates strongly depends on the crescent curvature. In contrast to aggregates of sufficiently-curved crescents that are capable of inducing full vesicle constriction, those of near flat crescents with negligible curvature leave the vesicle unconstricted. Our results offer promising perspectives for designing membrane-constricting nano structures such as nanoparticle aggregates and clusters of synthetic curved proteins such as DNA origami scaffolds with applications in synthetic biology. Our findings reveal the significant contribution of highly-curved F-BAR domains to cell division and explain how contractile protein rings such as dynamin GTPase, actomyosin rings, and endosomal sorting complexes required for transport constrict the membrane.

Curvature-Mediated Assembly of Janus Nanoparticles on Membrane Vesicles.

Besides direct particle-particle interactions, nanoparticles adsorbed to biomembranes experience indirect interactions that are mediated by the membrane curvature arising from particle adsorption. In this Letter, we show that the curvature-mediated interactions of adsorbed Janus particles depend on the initial curvature of the membrane prior to adsorption, that is, on whether the membrane initially bulges toward or away from the particles in our simulations. The curvature-mediated interaction can be strongly attractive for Janus particles adsorbed to the outside of a membrane vesicle, which initially bulges away from the particles. For Janus particles adsorbed to the vesicle inside, in contrast, the curvature-mediated interactions are repulsive. We find that the area fraction of the adhesive Janus particle surface is an important control parameter for the curvature-mediated interaction and assembly of the particles, besides the initial membrane curvature.

Scaffolding the cup-shaped double membrane in autophagy.

Autophagy is a physiological process for the recycling and degradation of cellular materials. Forming the autophagosome from the phagophore, a cup-shaped double-membrane vesicle, is a critical step in autophagy. The origin of the cup shape of the phagophore is poorly understood. In yeast, fusion of a small number of Atg9-containing vesicles is considered a key step in autophagosome biogenesis, aided by Atg1 complexes (ULK1 in mammals) localized at the preautophagosomal structure (PAS). In particular, the S-shaped Atg17-Atg31-Atg29 subcomplex of Atg1 is critical for phagophore nucleation at the PAS. To study this process, we simulated membrane remodeling processes in the presence and absence of membrane associated Atg17. We show that at least three vesicles need to fuse to induce the phagophore shape, consistent with experimental observations. However, fusion alone is not sufficient. Interactions with 34-nm long, S-shaped Atg17 complexes are required to overcome a substantial kinetic barrier in the transition to the cup-shaped phagophore. Our finding rationalizes the recruitment of Atg17 complexes to the yeast PAS, and their unusual shape. In control simulations without Atg17, with weakly binding Atg17, or with straight instead of S-shaped Atg17, the membrane shape transition did not occur. We confirm the critical role of Atg17-membrane interactions experimentally by showing that mutations of putative membrane interaction sites result in reduction or loss of autophagic activity in yeast. Fusion of a small number of vesicles followed by Atg17-guided membrane shape-remodeling thus emerges as a viable route to phagophore formation.

Rhinocerebral mucormycosis, risk factors and the type of oral manifestations in patients referred to a University Hospital in Tabriz, Iran 2007-2017.

Inadequate data are available on the global epidemiology of mucormycosis, mainly derived from the evaluation of specific population groups. Rhinocerebral mucormycosis is an invading and fatal mycosis, particularly among diabetic patients. In the present study, patients hospitalised in Imam Reza Hospital in Tabriz, from 2007 to 2017, were evaluated. The hospital information system (HIS) was used to collect the records of the patients. A total of 42 patients with a diagnosis of mucormycosis were included in the study, 40 cases (95%) of which had a diagnosis of the rhinocerebral form. Of these 40 patients, 21 (52.5%) and 19 (47.5%) were male and female, respectively. Seven cases (17.5%) of rhinocerebral mucormycosis were due to dental procedures. The most predisposing factor in the patients was diabetes with 36 (90%) cases. In our study, the role of tooth extraction in patients with uncontrolled diabetes was identified as an important factor. It may show the important role of dentists in preventing of the disease in diabetic patients.

The role of membrane curvature for the wrapping of nanoparticles.

Cellular internalization of nanoparticles requires the full wrapping of the nanoparticles by the cell membrane. This wrapping process can occur spontaneously if the adhesive interactions between the nanoparticles and the membranes are sufficiently strong to compensate for the cost of membrane bending. In this article, we show that the membrane curvature prior to wrapping plays a key role for the wrapping process, besides the size and shape of the nanoparticles that have been investigated in recent years. For membrane segments that initially bulge away from nanoparticles by having a mean curvature of the same sign as the mean curvature of the particle surface, we find strongly stable partially wrapped states that can prevent full wrapping. For membrane segments that initially bulge towards the nanoparticles, in contrast, partially wrapped states can constitute a significant energetic barrier for the wrapping process.

Electron scattering at a potential temporal step discontinuity.

We solve the problem of electron scattering at a potential temporal step discontinuity. For this purpose, instead of the Schrödinger equation, we use the Dirac equation, for access to back-scattering and relativistic solutions. We show that back-scattering, which is associated with gauge symmetry breaking, requires a vector potential, whereas a scalar potential induces only Aharonov-Bohm type energy transitions. We derive the scattering probabilities, which are found to be of later-forward and later-backward nature, with the later-backward wave being a relativistic effect, and compare the results with those for the spatial step and classical electromagnetic counterparts of the problem. Given the unrealizability of an infinitely sharp temporal discontinuity-which is of the same nature as its spatial counterpart!-we also provide solutions for a smooth potential step and demonstrate that the same physics as for the infinitely sharp case is obtained when the duration of the potential transition is sufficiently smaller than the de Broglie period of the electron (or deeply sub-period).

A case report of Tumor-Induced Osteomalacia (TIO) caused by central giant cell granuloma.

Introduction: Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome defined by severe hypophosphatemia, bone loss, fractures, and muscle weakness. Identifying of the tumor site is often difficult. The primary treatment for Tumor-induced osteomalacia (TIO) is currently surgical resection. Removing the primary tumor is the most definitive treatment for this disease. Methods: Here we describe the case of a 32-year-old man who exhibited sever muscle weakness and pain that had continued for three years. The patient has three sisters and one brother, all of whom are completely healthy and free of bone and muscle problems.Laboratory data indicate low serum phosphorus, normal serum and urine calcium level, besides raised alkaline phosphatase level. Due to elevated phosphorus levels in the urine and the lack of an alternative source for phosphorus excretion, along with the absence of short stature, bone deformities, and a negative family history that might suggest the potential for Tumor-induced osteomalacia (TIO), an octreotide scan was performed to the localized the tumor site. The scan, corroborated by CT and MRI scans, displayed absorption in the right maxillary sinus. Surgical excision of the lesion confirmed it to be a central giant cell granuloma. Results: Following surgery and without receiving any other treatment, the patient's phosphorus levels and clinical condition improved compared to before the surgical treatment. Subsequently, the symptoms of muscle weakness and skeletal pain significantly diminished, and the patient regained the ability to move. Conclusion: Tumor enucleation was conducted, and the pathological examination of the maxillary sinus lesion unveiled a central Giant cell granuloma. The patient had clinical and laboratory improvement after surgery. This finding confirmed our diagnosis of a paraneoplastic hypophosphatemia associated with a giant cell granuloma.

Increased burden of rare risk variants across gene expression networks predisposes to sporadic Parkinson's disease.

Alpha-synuclein (αSyn) is an intrinsically disordered protein that accumulates in the brains of patients with Parkinson's disease and forms intraneuronal inclusions called Lewy Bodies. While the mechanism underlying the dysregulation of αSyn in Parkinson's disease is unclear, it is thought that prionoid cell-to-cell propagation of αSyn has an important role. Through a high throughput screen, we recently identified 38 genes whose knock down modulates αSyn propagation. Follow up experiments were undertaken for two of those genes, TAX1BP1 and ADAMTS19, to study the mechanism with which they regulate αSyn homeostasis. We used a recently developed M17D neuroblastoma cell line expressing triple mutant (E35K+E46K+E61K) "3K" αSyn under doxycycline induction. 3K αSyn spontaneously forms inclusions that show ultrastructural similarities to Lewy Bodies. Experiments using that cell line showed that TAX1BP1 and ADAMTS19 regulate how αSyn interacts with lipids and phase separates into inclusions, respectively, adding to the growing body of evidence implicating those processes in Parkinson's disease. Through RNA sequencing, we identified several genes that are differentially expressed after knock-down of TAX1BP1 or ADAMTS19. Burden analysis revealed that those differentially expressed genes (DEGs) carry an increased frequency of rare risk variants in Parkinson's disease patients versus healthy controls, an effect that was independently replicated across two separate cohorts (GP2 and AMP-PD). Weighted gene co-expression network analysis (WGCNA) showed that the DEGs cluster within modules in regions of the brain that develop high degrees of αSyn pathology (basal ganglia, cortex). We propose a novel model for the genetic architecture of sporadic Parkinson's disease: increased burden of risk variants across genetic networks dysregulates pathways underlying αSyn homeostasis, thereby leading to pathology and neurodegeneration.

Tubulation and aggregation of spherical nanoparticles adsorbed on vesicles.

How nanoparticles interact with biomembranes is central for understanding their bioactivity. In this Letter, we report novel tubular membrane structures induced by adsorbed spherical nanoparticles, which we obtain from energy minimization. The membrane tubules enclose linear aggregates of particles and protrude into the vesicles. The high stability of the particle-filled tubules implies strongly attractive, membrane-mediated interactions between the particles. The tubular structures may provide a new route to encapsulate nanoparticles reversibly in vesicles.

Compartmentalizing and sculpting nanovesicles by phase-separated aqueous nanodroplets.

Phase-separated liquid droplets inside giant vesicles have been intensely studied as biomimetic model systems to understand cellular microcompartmentation and molecular crowding and sorting. On the nanoscale, however, how aqueous nanodroplets interact with and shape nanovesicles is poorly understood. We perform coarse-grained molecular simulations to explore the architecture of compartmentalized nanovesicles by phase-separated aqueous nanodroplets, and their morphological evolution under osmotic deflation. We show that phase separation of a biphasic liquid mixture can form both stable two-compartment and meta-stable multi-compartment nanovesicles. We identify morphological transitions of stable two-compartment nanovesicles between tube, sheet and cup morphologies, characterized by membrane asymmetry and phase-separation propensity between the aqueous phases. We demonstrate that the formation of local sheets and in turn cup-shaped nanovesicles is promoted by negative line tensions resulting from large separation propensities, an exclusive nanoscale phenomenon which is not expected for larger vesicles where energetic contributions of the line tensions are dominated by those of the membrane tensions. Despite their instability, we observe long-lived multi-compartment nanovesicles, such as nanotubules and branched tubules, whose prolonged lifetime is attributed to interfacial tensions and membrane asymmetry. Aqueous nanodroplets can thus form novel membrane nanostructures, crucial for cellular processes and forming cellular organelles on the nanoscale.

What hematological and endocrinal indicators are important in COVID-19 infection?

Background: Clinical evidence of endocrine involvement in coronavirus disease needs further investigation. The aim of the present study was to assess the relationship between hematology and endocrine parameters in coronavirus disease 2019 (COVID-19) infection. Methods: In the present cross-sectional study, a total of 320 patients (215 survivors and 105 non-survivors) with confirmed COVID-19 infection were enrolled. After isolation of serum samples, hematological, biochemical, and hormonal parameters were analyzed. Results: The mean age of survivors and non-survivors was 58.92 (SD: 15.28) and 63.65 (SD: 16.62) years, respectively. The results demonstrated significant differences in free triiodothyronine (FT3) [MD (95% CI): 0.40 (0.10, 0.71), P=0.009], total calcium [MD (95% CI): 0.53 (0.21, 0.86), P=0.003], vitamin D [MD (95% CI): 7.72 (6.38, 9.05), P=0.003], erythrocyte sedimentation rate (ESR) [MD (95% CI): 17.09 (9.38, 22.05), P=0.004) and serum ferritin [Median difference: -1091.9, P<0.001), between survivors and non-survivors, respectively. Conclusion: The results revealed that some hematological and endocrine factors play an important role in prognosis of COVID-19 infection. However, further studies with a larger population are required to clarify the exact effects of COVID-19 on the endocrine system.

Vesicle deformations by clusters of transmembrane proteins.

We carry out a coarse-grained molecular dynamics simulation of phospholipid vesicles with transmembrane proteins. We measure the mean and Gaussian curvatures of our protein-embedded vesicles and quantitatively show how protein clusters change the shapes of their host vesicles. The effects of depletion force and vesiculation on protein clustering are also investigated. By increasing the protein concentration, clusters are fragmented to smaller bundles, which are then redistributed to form more symmetric structures corresponding to lower bending energies. Big clusters and highly aspherical vesicles cannot be formed when the fraction of protein to lipid molecules is large.

The Relationship between Coronavirus Anxiety, Mindfulness and Spiritual Health in Patients with Cancer: A Survey in Southeast Iran.

OBJECTIVE: The sudden outbreak of COVID-19 has caused major health problems, including anxiety in cancer patients worldwide. Spiritual health and mindfulness are considered as factors affecting anxiety. This study addressed the relationship between COVID-19 anxiety, spiritual health and mindfulness in patients with cancer. METHODS: One hundred and eighty-four cancer patients participated in this cross-sectional study. The data were collected with convenience sampling method from two oncology centers from 15 June to 15 July 2020 in the southeast Iran. Patients completed the Demographic and Clinical Characteristics Form, Corona Disease Anxiety Scale (CDAS), The Freiburg Mindfulness inventory-Short Form (FMI-SF) and Spiritual Health Scale. RESULTS: According to the psychological symptom subscale (CDAS), 61.4% of the participants had moderate to severe anxiety. According to the physical symptom subscale, 38% of the participants had moderate to severe anxiety. No significant association was found between corona disease anxiety and mindfulness/spiritual health (p>0.05). CONCLUSION: The results of this study showed high levels of mental and physical anxiety and worries about COVID-19 disease in cancer patients, which led to challenges in their lives. It is necessary to review and implement effective interventions in future studies to prevent anxiety and its consequences in cancer patients.

Median 10 years follow-up of patients with covert Cushing's syndrome: a case series.

BACKGROUND: Ectopic adrenocorticotropic hormone secretion syndrome occurs in 10% of all patients with adrenocorticotropic-hormone-dependent hypercortisolism. It is usually associated with overt malignancies or with occult and indolent tumors. This study aims to confirm the source of ectopic adrenocorticotropic hormone in four patients with ectopic Cushing's syndrome over time. CASE PRESENTATION: A 38-year-old Iranian man with Cushing's syndrome underwent bilateral adrenalectomy since the source of ectopic adrenocorticotropic hormone secretion was not localized and pituitary imaging was normal. A whole-body scan revealed a right-lung tumoral mass with mediastinal lymph node metastasis. The mass was assumed a lung carcinoid tumor with mediastinal adenopathy. Right-lung mid-zone lobectomy and mediastinal lymphadenectomy were done. In a 47-year-old Iranian man with Cushing's syndrome, whole-body computed tomography scan revealed a pulmonary nodule in the posterior segment of the left lower lobe of the lung. The third case was a 25-year-old Iranian man who presented with symptoms and signs of Cushing's syndrome. Pituitary magnetic resonance imaging revealed a microadenoma 5 × 9 mm. Whole-body scan showed abnormal focal somatostatin receptors analog avid lesion in the posterior aspect of inferior third of right lung, highly suggestive of ectopic adrenocorticotropic-hormone-producing tumor. The last case was a 43-year-old Iranian woman with Marfan syndrome with a history of mitral and aortic valve replacement and chronic dissection of the aorta, who presented with symptoms and signs of Cushing's syndrome. She underwent bilateral adrenalectomy 1 year later owing to failure to locate ectopic adrenocorticotropic hormone syndrome. Whole-body scan showed abnormally increased radiotracer uptake in the midline of the skull base and posterior aspect of the middle zone of left hemithorax and bed of left lobe of thyroid. CONCLUSION: The clinical spectrum of ectopic adrenocorticotropic hormone secretion syndrome is wide, and distinguishing Cushing's disease from ectopic adrenocorticotropic hormone secretion syndrome is difficult. Initial failure to identify a tumor is common. Pulmonary carcinoid or occult source of ectopic adrenocorticotropic hormone secretion syndrome is usually the cause. In occult cases of ectopic adrenocorticotropic hormone in which the tumor cannot be localized, serial follow-up with serial computed tomography, magnetic resonance imaging, or scintigraphy is recommended for several years until the tumor can be localized and treated.

Nanoscopic spontaneous motion of liquid trains: Nonequilibrium molecular dynamics simulation.

Macroscale experiments show that a train of two immiscible liquid drops, a bislug, can spontaneously move in a capillary tube because of surface tension asymmetries. We use molecular dynamics simulation of Lennard-Jones fluids to demonstrate this phenomenon for NVT ensembles in submicron tubes. We deliberately tune the strength of intermolecular forces and control the velocity of bislug in different wetting and viscosity conditions. We compute the velocity profile of particles across the tube and explain the origin of deviations from the classical parabolae. We show that the self-generated molecular flow resembles the Poiseuille law when the ratio of the tube radius to its length is less than a critical value.

The safety and efficacy of biphasic insulin aspart 30 (BIAsp 30) in Iranians with type 2 diabetes: an open-label, non-randomised, multi-centre observational study--the Iran subgroup of the IMPROVE™ study.

INTRODUCTION: To evaluate the clinical profile of BIAsp 30 (30% soluble insulin aspart, 70% protamine-crystallized insulin aspart) (NovoMix®)30) in type 2 diabetes patients in routine clinical practice in Iran. MATERIAL AND METHODS: IMPROVE™ was a 26-week, multinational, open-label, non-randomized study in patients with type 2 diabetes. The safety and efficacy of BIAsp 30 were assessed at baseline and at 13 and 26 weeks. The titration of BIAsp30 was at the physician's discretion. RESULTS: In Iran, 478 patients (47% male) previously treated with oral antidiabetic drugs (OADs) (N = 159, 33.3%) and/or insulin other than BIAsp30 (N = 317, 66.3%) or a few who were treatment-naïve (N = 2, 0.4%) participated in the study. After 26 weeks of treatment with BIAsp 30, the rate of reported major hypoglycaemic episodes was reduced by 88.1% from baseline (baseline v. Week 26: 0.303 v. 0.037 episodes/pt-year; p < 0.001). No significant differences in minor hypoglycaemic episodes between baseline and Week 26 were found. Glycaemic control was significantly improved from baseline to Week 26 with a mean HbA(1c) reduction of 1.2 +/- 1.9%. Patients' quality of life as measured by the DiabMedSat questionnaire significantly improved from baseline (58.1) to the end of the study (75.4, p < 0.001). CONCLUSIONS: BIAsp 30 therapy appeared safe and effective and improved quality of life in Iranian patients with type 2 diabetes after 26 weeks of treatment.