Identification of dysregulation of sphingolipids in retinoblastoma using liquid chromatography-mass spectrometry.

Retinoblastoma (RB) is a rare ocular cancer seen in children that counts for approximately 3% of all childhood cancers. It is found that mutation in RB1, a tumour Suppressor Gene on chromosome 13 as the cause of malignancy. Retinoblastoma protein is the target for ceramide to cause apoptosis. We studied lipidomics of two RB cell lines, one aggressive cell line (NCC-RbC-51) derived from a metastatic site and one non aggressive cell line (WERI-Rb1) in comparison with a control cell line (MIO-M1). Lipid profiles of all the cell lines were studied using high resolution mass spectrometer coupled to high performance liquid chromatography. Data acquired from all the three cell lines in positive mode were analyzed to identify differentially expressed metabolites. Several phospholipids and lysophospholipids were found to be dysregulated. We observed upregulation of hexosyl ceramides, and down regulation of dihydroceramides and higher order sphingoglycolipids hinting at a hindered sphingolipid biosynthesis. The results obtained from liquid chromatography-mass spectrometry are validated by using qPCR and it was observed that genes involved in ceramide biosynthesis pathway are getting down regulated.

Quantum Mpemba Effect in a Quantum Dot with Reservoirs.

We demonstrate the quantum Mpemba effect in a quantum dot coupled to two reservoirs, described by the Anderson model. We show that the system temperatures starting from two different initial values (hot and cold) cross each other at finite time (and thereby reverse their identities; i.e., hot becomes cold and vice versa) to generate thermal quantum Mpemba effect. The slowest relaxation mode believed to play the dominating role in Mpemba effect in Markovian systems does not contribute to such anomalous relaxation in the present model. In this connection, our analytical result provides necessary condition for producing quantum Mpemba effect in the density matrix elements of the quantum dot, as a combined effect of the remaining relaxation modes.

Comparative analysis of image pre-filtering techniques for phase-shifted noise-affected interferograms.

Phase-shifting techniques are one of the most promising strategies to extract the phase information and retrieve the parameters of interest (e.g., refractive index, beam collimation, object shape, deformations, thickness, focal length, etc.) from interferograms. However, traditional phase-shifting techniques suffer from both internal and external noise, which reduce measurement accuracy. This paper reports a comparative analysis of the three commonly used filtering techniques, namely, Fourier, windowed Fourier, and wavelet filtering for noise reduction and accurate extraction of phase information from phase-shifted interferograms. Toward this, two basic types of noise (additive and multiplicative noise) are introduced in the simulated interferograms and processed using the pre-filtering strategies. The effect of second-order harmonics in the presence of noise is also examined. In addition, experimental demonstrations of the real-life applicability of the analyses are provided using the interferograms recorded on coherent (Talbot) and incoherent (Lau) grating shearing interferometers. High accuracy in the measurement of defocusing error of the lens is obtained using the filtering strategies. Further inferences and insights are drawn in favor of the pre-filtering techniques.

Anti-A and anti-B titers in A, B and O whole blood donors: Beyond "dangerous O".

BACKGROUND AND OBJECTIVES: Hemolytic transfusion reactions (HTRs) pose significant risks in transfused patients, with anti-A and anti-B antibodies in donor plasma being potential contributing factors. Despite advancements in component preparation, HTRs remain a concern, particularly with apheresis-derived platelets. This study aimed to determine the prevalence of high anti-A and anti-B titers among A, B, and O blood group donors and to explore factors associated with high titers. MATERIALS AND METHODS: A cross-sectional observational study was conducted over 18 months, enrolling 978 participants from a tertiary care teaching hospital in Western India. Anti-A and anti-B titers were determined using the Conventional Tube Technique (CTT). Statistical analysis assessed correlations between high titers and demographic factors. RESULTS: The majority of participants were young males (98.8%). Prevalence of high titers for IgM anti-A was 12.2% and IgG anti-A was 2.5%. For anti-B, IgM titers were 2.3% and IgG titers were 0.2%. The prevalence of dangerous O was found to be 14.1%, while 3.52% and 10.5% of A and B blood group donors were found to have high titers, respectively. Factors associated with high titers included female gender, vegetarian diet, age <30 years, and O blood group. CONCLUSION: The study sheds additional light and provides supplementary information regarding the prevalence and correlation of high anti-A and anti-B titers among O, A and B blood donors. Understanding these factors is crucial for optimizing transfusion safety protocols, including selective screening of platelet units and tailored transfusion strategies based on donor characteristics.

Harnessing the potential of blood donors negative for high prevalence Rh antigens: A database initiative for thalassaemia care.

BACKGROUND AND OBJECTIVES: With increasing life expectancy and prevalence of thalassaemia, it has led to a greater need for safe blood, yet the current supply from voluntary donors is insufficient to meet this demand. Thalassaemia recipients face a significant risk of alloimmunization because of repeated exposure to foreign red cell antigens. Study aims to determine high prevalent Rh antigen negative donors in western India donor population along with what percentage of these donors are willing to become dedicated voluntary donors for thalassaemia patients. Study also aims to examine factors influencing their willingness and challenges faced in mobilizing dedicated donors. METHOD: 700 whole blood donors from western India, following screening for inclusion & exclusion criteria as per Drugs and Cosmetic Act (DCA) 2020 amendment guidelines & were sero-negative for transfusion transmitted infections were enrolled for the study. Red cell phenotyping was performed using Conventional Tube Technique (CTT) for "D", "C", "E", "c", "e" and "K" antigen using known antisera. Donors that were "C" AND/OR "e" antigen negative were contacted telephonically and were counseled and motivated for becoming voluntary blood donors. Statistical analysis assessed correlation between donation frequency, donor's occupation and education. RESULT: Among 700 donors, 96.6% (n = 676) were males and 3.4% (n = 24) were females. The most predominant blood group was B > O > A > AB. Rh(D) antigen was present in 91.44% (n = 640) and absent in 8.6% (n = 60). Prevalence of other Rh antigens is as follows: "e" (99%) > "C" (85.4%) > "c" (59.1%) > "E" (18.0%). Only 1.15% had "K" antigen positive. The commonest Rh phenotype R1R1 (DCe/DCe) was expressed by 40.57% (n = 283), and the least common r″r (cE/ce), r″r″ (cE/cE) and r'r' (Ce/Ce) was found in 0.14% (n = 1), respectively. 'C' negative, 'e' negative, 'C' and 'e' antigen negative donors constituted 14.8% (n = 104) with 93.2% (n = 97) C-antigen negative, 1.92% (n = 2) e-antigen negative and 4.8% (n = 5) both "C" and "e" antigen negative donors. The commonest phenotypes among C-antigen and e-antigen negative donors were rr (50%) and RzR2 (1.94%) respectively. Likewise, the most common phenotype amongst both C- and e-antigens negative donors was R2R2 (3.84%). 61.5% of the donors agreed to enroll for voluntary blood donation following telephonic invitation, while 6.8% of them refused permanently. Approximately, 3.9% of the blood donors were willing to donate blood only when needed and 27.8% of them could not be contacted. CONCLUSION: Creating a database of voluntary donors with known phenotype, especially who lack very common antigens like "C" and "e" and are willing to become dedicated, regular voluntary donors for thalassemic patients can ensure timely administration of safe blood. One of the major challenges for this noble initiative was lack of awareness which can be circumvent effectively with proper counseling efforts.

Human iPSC-based disease modeling studies identify a common mechanistic defect and potential therapies for AMD and related macular dystrophies.

Age-related macular degeneration (AMD) and related macular dystrophies (MDs) primarily affect the retinal pigment epithelium (RPE) in the eye. A hallmark of AMD/MDs that drives later-stage pathologies is drusen. Drusen are sub-RPE lipid-protein-rich extracellular deposits, but how drusen forms and accumulates is not known. We utilized human induced pluripotent stem cell (iPSC)-derived RPE from patients with AMD and three distinct MDs to demonstrate that reduced activity of RPE-secreted matrix metalloproteinase 2 (MMP2) contributes to drusen in multiple maculopathies in a genotype-agnostic manner by instigating sterile inflammation and impaired lipid homeostasis via damage-associated molecular pattern molecule (DAMP)-mediated activation of receptor for advanced glycation end-products (RAGE) and increased secretory phospholipase 2-IIA (sPLA2-IIA) levels. Therapeutically, RPE-specific MMP2 supplementation, RAGE-antagonistic peptide, and a small molecule inhibitor of sPLA2-IIA ameliorated drusen accumulation in AMD/MD iPSC-RPE. Ultimately, this study defines a causal role of the MMP2-DAMP-RAGE-sPLA2-IIA axis in AMD/MDs.

The LTAR Croplands Common Experiment at Upper Mississippi River Basin-Ames.

Agricultural systems evolve from the interactions of climate, crops, soils, management practices (e.g., tillage, cover crops, nutrient management), and economic risks and rewards. Alternatives to the corn (Zea mays L.)-soybean [Glycine max (L.) Merr.] (C-S) cropping systems that dominate in the US Midwest may provide more sustainable use of resources, reduce the documented environmental impacts of current C-S systems, and improve production efficiency and ecosystem services. Innovative management practices are needed to offer producers options to increase farm resilience to variable weather conditions and offset negative environmental impacts. In response to this need, the Upper Mississippi River Basin Long-Term Agroecosystem Research network site at Ames, IA, established a cropland experiment in 2016 to investigate an alternative crop management system that includes reduced tillage, cover crops, and right source, right rate, right time, and right place (4R) nitrogen (N) management. The experimental site is located on the Iowa State University Kelley Research Farm in Boone County, IA. Crop, soil, air, and tile drainage water measurements are made throughout the year using published methods for each agronomic and environmental metric. Our goal is to provide quantitative information to farmers, consultants, agribusiness partners, and state and federal agencies to help guide decisions on the effective use of alternative management practices. Future changes in experimental treatments will adopt a knowledge co-production approach whereby researchers and stakeholders will work collaboratively to identify problems, implement research protocols, and interpret results.

Extracellular vesicles: an emerging player in retinal homeostasis.

Extracellular vesicles (EVs) encompass secreted membrane vesicles of varied sizes, including exosomes (-30-200 nm) and microvesicles (MVs) that are ∼100-1,000 nm in size. EVs play an important role in autocrine, paracrine, and endocrine signaling and are implicated in myriad human disorders including prominent retinal degenerative diseases, like age related macular degeneration (AMD) and diabetic retinopathy (DR). Studies of EVs in vitro using transformed cell lines, primary cultures, and more recently, induced pluripotent stem cell derived retinal cell type(s) (e.g., retinal pigment epithelium) have provided insights into the composition and function of EVs in the retina. Furthermore, consistent with a causal role of EVs in retinal degenerative diseases, altering EV composition has promoted pro-retinopathy cellular and molecular events in both in vitro and in vivo models. In this review, we summarize the current understanding of the role of EVs in retinal (patho)physiology. Specifically, we will focus on disease-associated EV alterations in specific retinal diseases. Furthermore, we discuss the potential utility of EVs in diagnostic and therapeutic strategies for targeting retinal diseases.

AMD recapitulated in a 3D biomimetic: A breakthrough in retina tissue engineering.

Song et al. (Nature Methods, 2022) engineered a 3D model of the human outer blood-retina barrier (oBRB) that recapitulates key features of healthy and age-related macular degeneration (AMD)-affected eyes.1 We shine a spotlight on this tissue-engineering triumph that has the potential to transform preclinical studies of AMD and other eye diseases.

Counterflow-induced clustering: Exact results.

We analyze the cluster formation in a nonergodic stochastic system as a result of counterflow, with the aid of an exactly solvable model. To illustrate the clustering, a two species asymmetric simple exclusion process with impurities on a periodic lattice is considered, where the impurity can activate flips between the two nonconserved species. Exact analytical results, supported by Monte Carlo simulations, show two distinct phases, free-flowing phase and clustering phase. The clustering phase is characterized by constant density and vanishing current of the nonconserved species, whereas the free-flowing phase is identified with nonmonotonic density and nonmonotonic finite current of the same. The n-point spatial correlation between n consecutive vacancies grows with increasing n in the clustering phase, indicating the formation of two macroscopic clusters in this phase, one of the vacancies and the other consisting of all the particles. We define a rearrangement parameter that permutes the ordering of particles in the initial configuration, keeping all the input parameters fixed. This rearrangement parameter reveals the significant effect of nonergodicity on the onset of clustering. For a special choice of the microscopic dynamics, we connect the present model to a system of run-and-tumble particles used to model active matter, where the two species having opposite net bias manifest the two possible run directions of the run-and-tumble particles, and the impurities act as tumbling reagents that enable the tumbling process.

Elucidating the Therapeutic Potential of Cell-Penetrating Peptides in Human Tenon Fibroblast Cells.

Cell-penetrating peptides (CPPs) have been widely used as vehicles for delivering therapeutic molecules to the site of action. Apart from their delivering potential, the biological effects of CPPs have not been explored in detail. JTS-1 is a CPP that has been reported to have gene delivery functions, although its biological role is yet to be determined. Hence, in this study, we revealed the biological mechanism such as its uptake mechanism and immunogenic potential and function using primary human tenon fibroblast (TF) cells collected from patients undergoing glaucoma trabeculectomy surgery. Our results showed that the JTS-1 peptide has an α-helical structure and is nontoxic up to 1 µM concentration. It was found to be colocalized with early endosome (Rab5), recycling endosome (Rab7), and Rab11 and interacted with major histocompatibility complex (MHC) class I and II. The peptide also affected actin polymerization, which is regulated by cofilin phosphorylation and ROCK1 localization. It also inhibited TF cell proliferation. Therefore, the JTS-1 peptide could be used as a possible therapeutic agent for modifying the fibrosis process, where TF proliferation is a key cause of surgery failure.

Dynamical regimes of finite-temperature discrete nonlinear Schrödinger chain.

We show that the one-dimensional discrete nonlinear Schrödinger chain (DNLS) at finite temperature has three different dynamical regimes (ultralow-, low-, and high-temperature regimes). This has been established via (i) one-point macroscopic thermodynamic observables (temperature T, energy density ε, and the relationship between them), (ii) emergence and disappearance of an additional almost conserved quantity (total phase difference), and (iii) classical out-of-time-ordered correlators and related quantities (butterfly speed and Lyapunov exponents). The crossover temperatures T_{l-ul} (between low- and ultra-low-temperature regimes) and T_{h-l} (between the high- and low-temperature regimes) extracted from these three different approaches are consistent with each other. The analysis presented here is an important step forward toward the understanding of DNLS which is ubiquitous in many fields and has a nonseparable Hamiltonian form. Our work also shows that the different methods used here can serve as important tools to identify dynamical regimes in other interacting many-body systems.

Spatiotemporal spread of perturbations in a driven dissipative Duffing chain: An out-of-time-ordered correlator approach.

Out-of-time-ordered correlators (OTOCs) have been extensively used as a major tool for exploring quantum chaos, and recently there has been a classical analog. Studies have been limited to closed systems. In this work, we probe an open classical many-body system, more specifically, a spatially extended driven dissipative chain of coupled Duffing oscillators using the classical OTOC to investigate the spread and growth (decay) of an initially localized perturbation in the chain. Correspondingly, we find three distinct types of dynamical behavior: the sustained chaos, transient chaos, and nonchaotic region, as clearly exhibited by different geometrical shapes in the OTOC heat map. To quantify such differences, we look at instantaneous speed (IS), finite-time Lyapunov exponents (FTLEs), and velocity-dependent Lyapunov exponents (VDLEs) extracted from OTOCs. Introduction of these quantities turns out to be instrumental in diagnosing and demarcating different regimes of dynamical behavior. To gain control over open nonlinear systems, it is important to look at the variation of these quantities with respect to parameters. As we tune drive, dissipation, and coupling, FTLEs and IS exhibit transition between sustained chaos and nonchaotic regimes with intermediate transient chaos regimes and highly intermittent sustained chaos points. In the limit of zero nonlinearity, we present exact analytical results for the driven dissipative harmonic system, and we find that our analytical results can very well describe the nonchaotic regime as well as the late-time behavior in the transient regime of the Duffing chain. We believe that this analysis is an important step forward towards understanding nonlinear dynamics, chaos, and spatiotemporal spread of perturbations in many-particle open systems.

Understanding the Uptake Mechanism and Interaction Potential of the Designed Peptide and Preparation of Composite Fiber Matrix for Fungal Keratitis.

The conventional use of antibiotics for the treatment of infectious keratitis currently faces two major challenges: poor drug penetration and the emergence of antibiotic resistance in microbial strains. Cell-penetrating peptides (CPPs) with antimicrobial properties have the potential to address these challenges. However, their mode of action, mechanism of uptake, and interaction potential have not been explored in detail. In this study, we probed the mechanism of uptake and interaction potential of our previously designed peptides (VRF005 and VRF007). Our results showed that VRF005 undergoes direct translocation and induces a rough membrane surface, whereas VRF007 undergoes clathrin-mediated endocytic uptake. The gel shift assay showed that VRF005 is bound to genomic DNA, whereas VRF007 is bound to chitin and ß-d-glucan. Gene expression studies revealed the effect of peptide VRF005 on Candida albicans transcription. Molecular docking and simulations showed that VRF005 forms noncovalent interactions (such as H-bonding and water bridges) with natamycin. It exhibited synergistic antifungal activity in the colony-forming assay. VRF005, functionalized in the polycaprolactone fiber matrix, showed sustained delivery and antifungal activity.

Risky driving among regular armed forces personnel from the United Kingdom.

BACKGROUND: Road traffic accidents are the leading cause of death for service personnel from the United Kingdom (UK). Little is known about the pattern of risky driving by these service personnel. METHODS: Cross-sectional data (collected postdeployment, between June 2004 and March 2006) were analyzed from a large, randomly selected cohort of military personnel from the UK. These analyses were limited to regular-service personnel who were drivers (n=8,127; 7,443 men and 684 women). "Risky driving" (not wearing a seatbelt, speeding, or both) was examined. Analyses were then repeated but restricted to those with experience of deployment to Iraq (n=4,611). All analyses were undertaken during 2007. RESULTS: Nineteen percent of armed forces personnel from the UK were defined as risky drivers. Risky driving was associated with being of young age; being male; being in the Army; childhood adversity; being deployed to Iraq; having a combat role; and being separated, divorced, or widowed. Restricting analyses to those deployed to Iraq revealed that risky driving was associated with increasing exposure to traumatic events and low in-theater morale. CONCLUSIONS: There are clear sociodemographic associations of risk-taking behaviors in the military population, and the study's results imply that risky driving is more common in drivers who had deployed.

Negative differential mobility in interacting particle systems.

Driven particles in the presence of crowded environment, obstacles, or kinetic constraints often exhibit negative differential mobility (NDM) due to their decreased dynamical activity. Based on the empirical studies of conserved lattice gas model, two species exclusion model and other interacting particle systems we propose a new mechanism for complex many-particle systems where slowing down of certain non-driven degrees of freedom by the external field can give rise to NDM. To prove that the slowing down of the non-driven degrees is indeed the underlying cause, we consider several driven diffusive systems including two species exclusion models, misanthrope process, and show from the exact steady state results that NDM indeed appears when some non-driven modes are slowed down deliberately. For clarity, we also provide a simple pedagogical example of two interacting random walkers on a ring which conforms to the proposed scenario.

Phase coexistence and spatial correlations in reconstituting k-mer models.

In reconstituting k-mer models, extended objects that occupy several sites on a one-dimensional lattice undergo directed or undirected diffusion, and reconstitute-when in contact-by transferring a single monomer unit from one k-mer to the other; the rates depend on the size of participating k-mers. This polydispersed system has two conserved quantities, the number of k-mers and the packing fraction. We provide a matrix product method to write the steady state of this model and to calculate the spatial correlation functions analytically. We show that for a constant reconstitution rate, the spatial correlation exhibits damped oscillations in some density regions separated, from other regions with exponential decay, by a disorder surface. In a specific limit, this constant-rate reconstitution model is equivalent to a single dimer model and exhibits a phase coexistence similar to the one observed earlier in totally asymmetric simple exclusion process on a ring with a defect.

Fate of over 480 million inhabitants living in arsenic and fluoride endemic Indian districts: Magnitude, health, socio-economic effects and mitigation approaches.

During our last 27 years of field survey in India, we have studied the magnitude of groundwater arsenic and fluoride contamination and its resulting health effects from numerous states. India is the worst groundwater fluoride and arsenic affected country in the world. Fluoride results the most prevalent groundwater related diseases in India. Out of a total 29 states in India, groundwater of 20 states is fluoride affected. Total population of fluoride endemic 201 districts of India is 411 million (40% of Indian population) and more than 66 million people are estimated to be suffering from fluorosis including 6 million children below 14 years of age. Fluoride may cause a crippling disease. In 6 states of the Ganga-Brahmaputra Plain (GB-Plain), 70.4 million people are potentially at risk from groundwater arsenic toxicity. Three additional states in the non GB-Plain are mildly arsenic affected. For arsenic with substantial cumulative exposure can aggravate the risk of cancers along with various other diseases. Clinical effects of fluoride includes abnormal tooth enamel in children; adults had joint pain and deformity of the limbs, spine etc. The affected population chronically exposed to arsenic and fluoride from groundwater is in danger and there is no available medicine for those suffering from the toxicity. Arsenic and fluoride safe water and nutritious food are suggested to prevent further aggravation of toxicity. The World Health Organization (WHO) points out that social problems arising from arsenic and fluoride toxicity eventually create pressure on the economy of the affected areas. In arsenic and fluoride affected areas in India, crisis is not always having too little safe water to satisfy our need, it is the crisis of managing the water.