How safe are nanoscale metal-organic frameworks?

Owing to the size scales that can be accessed, the nanoscale has opened doors to new physical and chemical properties, not seen in the bulk. These properties are leveraged by nanomaterials (NMs) across a plethora of applications. More recently, nanoscale metal-organic frameworks (nMOFs) have witnessed explosive growth due to the modularity of their chemical constituents, the ability to modify their composition and structure, and exceptional properties such as permanent porosity and high surface areas. These properties have prompted the investigation of these materials for applications in biological and environmental contexts. However, one aspect that is often ignored in these discussions is their safety at a nanoscale. In this mini review, we aim to initiate a discussion on the safety and toxicity of nMOFs, drawing parallels with the existing guidelines and literature on the safety of inorganic NMs. We first describe why nMOFs are of considerable interest to the scientific community followed by a discussion on routes through which they can be exposed to the environment and living organisms, particularly shedding light on their transformation mechanisms. The review also discusses the factors affecting toxicity of nMOFs, such as their size, shape, morphology, and composition. We briefly highlight potential mechanisms of toxicity and conclude with describing the need to transition towards data-intensive computational approaches such as machine learning to establish nMOFs as credible materials for their envisioned applications

Investigation of Structural Parameter Variation on Extended Gate TFET for Bio-Sensor Applications

Traditional Gate engineered Metal Oxide Semiconductor (MOS) technology faced serious challenges in terms of greater sensitivity for target biomolecules and to be utilized as the state-of-the-art Nano-recognition tool. Research on a tunnel field-effect transistor (TFET) started with the aim to achieve fast detection, low power consumption, and its potential for on-chip integration capability. Dielectric Modulated TFET (DMTFET) has established itself to be a primary candidate for sensing both charged and charge-neutral species with volumetric sensitivity. As extended gate DMTFET happens to be inferior to its short gate counterpart, we have devised ways to achieve superior performance only by making variations over structural electrostatics. With the incorporation of most possible ways of modulation, we present two orders of magnitude on-current increment and a considerable percentage of sensitivity improvement over the conventional one. Future scopes having noteworthy diversifications have also been analyzed with proper justification

Modulation of Heat Shock Protein Expression in Alveolar Adenocarcinoma Cells through Gold Nanoparticles and Cisplatin Treatment

Heat-shock proteins (HSPs) are stress-responsive molecules belonging to the family of evolutionary molecular chaperones known to be crucial in many cancer types, including human alveolar adenocarcinoma cells (A549). These proteins are highly overexpressed in cancers to support their ability to accommodate imbalances in cell signalling, DNA alterations, proteins, and energy metabolism associated with oncogenesis. The current study evaluated the effects of gold nanoparticles (AuNPs) combined with cisplatin (CDDP) on molecular chaperone HSPs in A549 cells. It was found that AuNPs:CDDP decreased the percentage of cell viability (38.5%) measured using the modified lactated dehydrogenase (mLDH) and 3-[4,5-dimethylthiazole-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assays. AuNPs:CDDP exposure caused a significant (p < 0.05) increase in reactive oxygen species (ROS) generation by 1.81-fold, apoptosis induction, and a decrease in the mitochondrial membrane potential (MMP) compared to AuNPs or CDDP alone. Similarly, exposure to the AuNPs:CDDP combination had pronounced cytotoxic effects on the expression of HSPs and PI3K/AKT/mTOR, as well as apoptosis-related proteins. The results demonstrate that the combination of AuNPs with CDDP might enhance the anticancer efficacy of CDDP

Gold Nanoparticles Induced Size Dependent Cytotoxicity on Human Alveolar Adenocarcinoma Cells by Inhibiting the Ubiquitin Proteasome System

Gold nanoparticles (AuNPs) are widely used in biomedicine due to their remarkable therapeutic applications. However, little is known about their cytotoxic effects on the ubiquitin proteasome system (UPS). Herein, the cytotoxicity of different sizes of AuNPs (5, 10, and 80 nm) on the UPS was investigated with a particular focus on deubiquitinating enzymes (DUBs) such as ubiquitin-specific proteases (USP) and ubiquitin carboxyl-terminal hydrolases (UCHL-1) in human alveolar epithelial adenocarcinoma (A549). It was found that all sizes of AuNPs reduced the percentage of viable A549 cells and increased lactate dehydrogenase (LDH) release, measured using the MTT and LDH assays, respectively. Furthermore, the 5 nm AuNPs were found to exhibit greater cytotoxicity than the 10 and 80 nm AuNPs. In addition, apoptosis and necrosis were activated through reactive oxygen species (ROS) generation due to AuNPs exposure. The internalisation of AuNPs in A549 cells increased with increasing particle size (80 > 10 > 5 nm). Interestingly, the expression of USP7, USP8, USP10, and UCHL-1 was significantly (p < 0.001) downregulated upon treatment with 5–30 µg/mL of all the AuNPs sizes compared to control cells. Moreover, the inhibition of these proteins triggered mitochondrial-related apoptosis through the upregulation of poly (ADP-ribose) polymerase (PARP), caspase-3, and caspase-9. Collectively, these results indicate that AuNPs suppress the proliferation of A549 cells and can potentially be used as novel inhibitors of the proteasome

TWO DIMENSIONAL VS THREE DIMENSIONAL VSP (VIRTUAL SURGICAL PLANNING) IN ORTHOGNATHIC SURGERY - A REVIEW

Orthodontic treatment provides a solution for the improvement of teeth alignment, facial aesthetics, functional and periodontal problems. Deformities that cannot be corrected with orthodontic treatment alone are called dentofacial deformities. This is where growth modification or orthognathic surgery comes into play. It is carried out in adults having severe dentofacial deformities. In order to have a successful outcome in patients undergoing orthognathic surgery, a meticulous treatment planning is required. 2 dimensional analysis has been conventionally used for orthognathic surgery treatment planning and outcome prediction. 2D planning consists of clinical examination, impressions, occlusal records, cephalometric analysis, face bow transfer, model surgery on plaster cast and fabrication of occlusal splints. &nbsp;But the attempt to recreate 3 dimensional structures through 2D tools is not extremely accurate, and has quite a few limitations, such as an ill fitting surgical splint. Hence over the years, 3 dimensional planning has been developed, in an attempt to make treatment prediction and outcomes for orthognathic surgery much more precise. Computer aided virtual surgical planning (VSP) offers an extremely accurate diagnosis, enhanced analysis of maxillofacial structures, and improved prectibability of post operative changes of hard and soft tissue

Does the doping strategy of ferrite nanoparticles create a correlation between reactivity and toxicity?

Owing to their remarkable properties in terms of electrical resistivity, chemical stability, and saturation magnetisation, ferrite nanoparticles are being increasingly used for a wide range of applications. This study looks to investigate as to whether ferrite nanoparticles can be safely and viably doped with transition metal elements without adversely affecting the stability and toxicity of the nanoparticles. Monodispersed and phase pure variants of ferrites (MxFe3−xO4 where M = Co, Cu, Zn, Mn) were synthesised with a size range of 9-11 nm using a wet chemistry route. The doping % within the ferrites was within the range of 15-18% for all the dopants. Compared to ferrite nanoparticles, Co and Mn doping significantly enhanced the dissolution, whereas doping with Cu and Zn had an opposite effect to dissolution. DFT calculations performed on the ferrites to calculate the vacancy formation energy of Fe and dopant atoms substantiated the experimental dissolution data. A549 cells showed a dose dependent response (10-200 μg mL−1) and the reduction in cell viability followed the trend of MnxFe3−xO4 &gt; CoxFe3−xO4 &gt; ZnxFe3−xO4 &gt; CuxFe3−xO4 &gt; Fe3O4. A correlation study between dissolution, cell viability and uptake indicated cell viability and dissolution had a strong negative correlation for Fe3O4, and CoxFe3−xO4 whereas for CuxFe3−xO4 this correlation was very weak. We conclude by providing an overview of the impact of doping on the safety of other metal-oxide nanoparticles (CuO, ZnO, TiO2 and CeO2) in comparison to ferrite nanoparticles.</p

Defects in the Outer Limiting Membrane Are Associated with Rosette Development in the Nrl−/− Retina

The neural retinal leucine zipper (Nrl) knockout mouse is a widely used model to study cone photoreceptor development, physiology, and molecular biology in the absence of rods. In the Nrl−/− retina, rods are converted into functional cone-like cells. The Nrl−/− retina is characterized by large undulations of the outer nuclear layer (ONL) commonly known as rosettes. Here we explore the mechanism of rosette development in the Nrl−/− retina. We report that rosettes first appear at postnatal day (P)8, and that the structure of nascent rosettes is morphologically distinct from what is seen in the adult retina. The lumen of these nascent rosettes contains a population of aberrant cells protruding into the subretinal space that induce infolding of the ONL. Morphologically adult rosettes do not contain any cell bodies and are first detected at P15. The cells found in nascent rosettes are photoreceptors in origin but lack inner and outer segments. We show that the adherens junctions between photoreceptors and Müller glia which comprise the retinal outer limiting membrane (OLM) are not uniformly formed in the Nrl−/− retina and thus allow protrusion of a population of developing photoreceptors into the subretinal space where their maturation becomes delayed. These data suggest that the rosettes of the Nrl−/− retina arise due to defects in the OLM and delayed maturation of a subset of photoreceptors, and that rods may play an important role in the proper formation of the OLM

Global burden of 288 causes of death and life expectancy decomposition in 204 countries and territories and 811 subnational locations, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

BACKGROUND Regular, detailed reporting on population health by underlying cause of death is fundamental for public health decision making. Cause-specific estimates of mortality and the subsequent effects on life expectancy worldwide are valuable metrics to gauge progress in reducing mortality rates. These estimates are particularly important following large-scale mortality spikes, such as the COVID-19 pandemic. When systematically analysed, mortality rates and life expectancy allow comparisons of the consequences of causes of death globally and over time, providing a nuanced understanding of the effect of these causes on global populations. METHODS The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 cause-of-death analysis estimated mortality and years of life lost (YLLs) from 288 causes of death by age-sex-location-year in 204 countries and territories and 811 subnational locations for each year from 1990 until 2021. The analysis used 56 604 data sources, including data from vital registration and verbal autopsy as well as surveys, censuses, surveillance systems, and cancer registries, among others. As with previous GBD rounds, cause-specific death rates for most causes were estimated using the Cause of Death Ensemble model-a modelling tool developed for GBD to assess the out-of-sample predictive validity of different statistical models and covariate permutations and combine those results to produce cause-specific mortality estimates-with alternative strategies adapted to model causes with insufficient data, substantial changes in reporting over the study period, or unusual epidemiology. YLLs were computed as the product of the number of deaths for each cause-age-sex-location-year and the standard life expectancy at each age. As part of the modelling process, uncertainty intervals (UIs) were generated using the 2·5th and 97·5th percentiles from a 1000-draw distribution for each metric. We decomposed life expectancy by cause of death, location, and year to show cause-specific effects on life expectancy from 1990 to 2021. We also used the coefficient of variation and the fraction of population affected by 90% of deaths to highlight concentrations of mortality. Findings are reported in counts and age-standardised rates. Methodological improvements for cause-of-death estimates in GBD 2021 include the expansion of under-5-years age group to include four new age groups, enhanced methods to account for stochastic variation of sparse data, and the inclusion of COVID-19 and other pandemic-related mortality-which includes excess mortality associated with the pandemic, excluding COVID-19, lower respiratory infections, measles, malaria, and pertussis. For this analysis, 199 new country-years of vital registration cause-of-death data, 5 country-years of surveillance data, 21 country-years of verbal autopsy data, and 94 country-years of other data types were added to those used in previous GBD rounds. FINDINGS The leading causes of age-standardised deaths globally were the same in 2019 as they were in 1990; in descending order, these were, ischaemic heart disease, stroke, chronic obstructive pulmonary disease, and lower respiratory infections. In 2021, however, COVID-19 replaced stroke as the second-leading age-standardised cause of death, with 94·0 deaths (95% UI 89·2-100·0) per 100 000 population. The COVID-19 pandemic shifted the rankings of the leading five causes, lowering stroke to the third-leading and chronic obstructive pulmonary disease to the fourth-leading position. In 2021, the highest age-standardised death rates from COVID-19 occurred in sub-Saharan Africa (271·0 deaths [250·1-290·7] per 100 000 population) and Latin America and the Caribbean (195·4 deaths [182·1-211·4] per 100 000 population). The lowest age-standardised death rates from COVID-19 were in the high-income super-region (48·1 deaths [47·4-48·8] per 100 000 population) and southeast Asia, east Asia, and Oceania (23·2 deaths [16·3-37·2] per 100 000 population). Globally, life expectancy steadily improved between 1990 and 2019 for 18 of the 22 investigated causes. Decomposition of global and regional life expectancy showed the positive effect that reductions in deaths from enteric infections, lower respiratory infections, stroke, and neonatal deaths, among others have contributed to improved survival over the study period. However, a net reduction of 1·6 years occurred in global life expectancy between 2019 and 2021, primarily due to increased death rates from COVID-19 and other pandemic-related mortality. Life expectancy was highly variable between super-regions over the study period, with southeast Asia, east Asia, and Oceania gaining 8·3 years (6·7-9·9) overall, while having the smallest reduction in life expectancy due to COVID-19 (0·4 years). The largest reduction in life expectancy due to COVID-19 occurred in Latin America and the Caribbean (3·6 years). Additionally, 53 of the 288 causes of death were highly concentrated in locations with less than 50% of the global population as of 2021, and these causes of death became progressively more concentrated since 1990, when only 44 causes showed this pattern. The concentration phenomenon is discussed heuristically with respect to enteric and lower respiratory infections, malaria, HIV/AIDS, neonatal disorders, tuberculosis, and measles. INTERPRETATION Long-standing gains in life expectancy and reductions in many of the leading causes of death have been disrupted by the COVID-19 pandemic, the adverse effects of which were spread unevenly among populations. Despite the pandemic, there has been continued progress in combatting several notable causes of death, leading to improved global life expectancy over the study period. Each of the seven GBD super-regions showed an overall improvement from 1990 and 2021, obscuring the negative effect in the years of the pandemic. Additionally, our findings regarding regional variation in causes of death driving increases in life expectancy hold clear policy utility. Analyses of shifting mortality trends reveal that several causes, once widespread globally, are now increasingly concentrated geographically. These changes in mortality concentration, alongside further investigation of changing risks, interventions, and relevant policy, present an important opportunity to deepen our understanding of mortality-reduction strategies. Examining patterns in mortality concentration might reveal areas where successful public health interventions have been implemented. Translating these successes to locations where certain causes of death remain entrenched can inform policies that work to improve life expectancy for people everywhere. FUNDING Bill & Melinda Gates Foundation