Arsenic and cadmium availability and its removal in paddy farming areas.

Arsenic (As) and cadmium (Cd) accumulation in rice grain is a global concern threatening food security and safety to the growing population. As and Cd are toxic non-essential elements poisonous to animal and human at higher levels. Its accumulation in agro-ecosystems pose a public health risk to consumers of agro-ecosystem products. Due to their hazards, As and Cd sources should be cleared, avoiding entering plants and the human body. As and Cd removal in soils and grains in agro-ecosystems has been conducted by various materials (natural and synthesized), however, there are little documentation on their contribution on As and Cd removal or reduction in rice grains. This identified knowledge gap necessitate a systematically review to understand efficiency and mechanisms of As and Cd availability reduction and removal in paddy farming areas through utilization of various synthetic and modified materials. To achieve this, published peer reviewed articles between 2010 and 2024 were collected from various database i.e., Science Direct, Web of Science, Google Scholar, and Research Gate and analyzed its content in respect to As and Cd reduction and removal. Furthermore, collected data were re-analyzed to determine standardized mean differences (SMD) with 95% confidence intervals (CI). Based on 96 studies with 228 observations involving Fe, Ca, Si, and Se-based materials were identified, it was found that application of Fe, Ca, Si, and Se-based materials potentially reduced As and Cd in rice grains among various study sites and across studies. Among the studied materials, Fe-based materials observed to be more efficient compared to other utilized materials. However, there little or no information on performance of materials when used in combination and how they can improve crop productivity and soil health, thus requiring further studies. Thus, this study confirm Fe, Ca, Si, and Se modified materials have significant potential to reduce As and Cd availability in paddy farming areas and rice grains, thus necessary effort must be made to ensure materials access and availability for farmers utilization in paddy fields to reduce As and Cd accumulation.

Intermittency in the not-so-smooth elastic turbulence.

Elastic turbulence is the chaotic fluid motion resulting from elastic instabilities due to the addition of polymers in small concentrations at very small Reynolds ( Re ) numbers. Our direct numerical simulations show that elastic turbulence, though a low Re phenomenon, has more in common with classical, Newtonian turbulence than previously thought. In particular, we find power-law spectra for kinetic energy E(k) ~ k-4 and polymeric energy Ep(k) ~ k-3/2, independent of the Deborah (De) number. This is further supported by calculation of scale-by-scale energy budget which shows a balance between the viscous term and the polymeric term in the momentum equation. In real space, as expected, the velocity field is smooth, i.e., the velocity difference across a length scale r, δu ~ r but, crucially, with a non-trivial sub-leading contribution r3/2 which we extract by using the second difference of velocity. The structure functions of second difference of velocity up to order 6 show clear evidence of intermittency/multifractality. We provide additional evidence in support of this intermittent nature by calculating moments of rate of dissipation of kinetic energy averaged over a ball of radius r, εr, from which we compute the multifractal spectrum.

Lipid Nanoparticle-Associated Inflammation is Triggered by Sensing of Endosomal Damage: Engineering Endosomal Escape Without Side Effects.

Lipid nanoparticles (LNPs) have emerged as the dominant platform for RNA delivery, based on their success in the COVID-19 vaccines and late-stage clinical studies in other indications. However, we and others have shown that LNPs induce severe inflammation, and massively aggravate pre-existing inflammation. Here, using structure-function screening of lipids and analyses of signaling pathways, we elucidate the mechanisms of LNP-associated inflammation and demonstrate solutions. We show that LNPs' hallmark feature, endosomal escape, which is necessary for RNA expression, also directly triggers inflammation by causing endosomal membrane damage. Large, irreparable, endosomal holes are recognized by cytosolic proteins called galectins, which bind to sugars on the inner endosomal membrane and then regulate downstream inflammation. We find that inhibition of galectins abrogates LNP-associated inflammation, both in vitro and in vivo . We show that rapidly biodegradable ionizable lipids can preferentially create endosomal holes that are smaller in size and reparable by the endosomal sorting complex required for transport (ESCRT) pathway. Ionizable lipids producing such ESCRT-recruiting endosomal holes can produce high expression from cargo mRNA with minimal inflammation. Finally, we show that both routes to non-inflammatory LNPs, either galectin inhibition or ESCRT-recruiting ionizable lipids, are compatible with therapeutic mRNAs that ameliorate inflammation in disease models. LNPs without galectin inhibition or biodegradable ionizable lipids lead to severe exacerbation of inflammation in these models. In summary, endosomal escape induces endosomal membrane damage that can lead to inflammation. However, the inflammation can be controlled by inhibiting galectins (large hole detectors) or by using biodegradable lipids, which create smaller holes that are reparable by the ESCRT pathway. These strategies should lead to generally safer LNPs that can be used to treat inflammatory diseases.

Combination of Physicochemical Tropism and Affinity Moiety Targeting of Lipid Nanoparticles Enhances Organ Targeting.

Two camps have emerged for targeting nanoparticles to specific organs and cell types: affinity moiety targeting and physicochemical tropism. Here we directly compare and combine both using intravenous (IV) lipid nanoparticles (LNPs) designed to target the lungs. We utilized PECAM antibodies as affinity moieties and cationic lipids for physicochemical tropism. These methods yield nearly identical lung uptake, but aPECAM LNPs show higher endothelial specificity. LNPs combining these targeting methods had >2-fold higher lung uptake than either method alone and markedly enhanced epithelial uptake. To determine if lung uptake is because the lungs are the first organ downstream of IV injection, we compared IV vs intra-arterial (IA) injection into the carotid artery, finding that IA combined-targeting LNPs achieve 35% of the injected dose per gram (%ID/g) in the first-pass organ, the brain, among the highest reported. Thus, combining the affinity moiety and physicochemical strategies provides benefits that neither targeting method achieves alone.

Organ-specific biotransformation in salmonids: Insight into intrinsic enzyme activity and biotransformation of three micropollutants.

Aquatic ecosystems continue to be threatened by chemical pollution. To what extent organisms are able to cope with chemical exposure depends on their ability to display mechanisms of defense across different organs. Among these mechanisms, biotransformation processes represent key physiological responses that facilitate detoxification and reduce the bioaccumulation potential of chemicals. Biotransformation does not only depend on the ability of different organs to display biotransformation enzymes but also on the affinity of chemicals towards these enzymes. In the present study, we explored the ability of different organs and of two freshwater fish to support biotransformation processes through the determination of in vitro phase I and II biotransformation enzyme activity, and their role in supporting intrinsic clearance and the formation of biotransformation products. Three environmentally relevant pollutants were evaluated: the polycyclic aromatic hydrocarbon (PAH) pyrene (as recommended by the OECD 319b test guideline), the fungicide azoxystrobin, and the pharmaceutical propranolol. Comparative studies using S9 sub-cellular fractions derived from the liver, intestine, gills, and brain of brown trout (Salmo trutta) and rainbow trout (Oncorhynchus mykiss) revealed significant phase I and II enzyme activity in all organs. However, organ- and species-specific differences were found. In brown trout, significant extrahepatic biotransformation was observed for pyrene but not for azoxystrobin and propranolol. In rainbow trout, the brain appeared to biotransform azoxystrobin. In this same species, propranolol appeared to be biotransformed by the intestine and gills. Biotransformation products could be detected only from hepatic biotransformation, and their profiles and formation rates displayed species-specific patterns and occurred at different magnitudes. Altogether, our findings further contribute to the current understanding of organ-specific biotransformation capacity, beyond the expression and activity of enzymes, and its dependence on specific enzyme-chemical interactions to support mechanisms of defense against exposure.

Antibody-independent protection against heterologous SARS-CoV-2 challenge conferred by prior infection or vaccination.

Vaccines have reduced severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) morbidity and mortality, yet emerging variants challenge their effectiveness. The prevailing approach to updating vaccines targets the antibody response, operating under the presumption that it is the primary defense mechanism following vaccination or infection. This perspective, however, can overlook the role of T cells, particularly when antibody levels are low or absent. Here we show, through studies in mouse models lacking antibodies but maintaining functional B cells and lymphoid organs, that immunity conferred by prior infection or mRNA vaccination can protect against SARS-CoV-2 challenge independently of antibodies. Our findings, using three distinct models inclusive of a novel human/mouse ACE2 hybrid, highlight that CD8+ T cells are essential for combating severe infections, whereas CD4+ T cells contribute to managing milder cases, with interferon-γ having an important function in this antibody-independent defense. These findings highlight the importance of T cell responses in vaccine development, urging a broader perspective on protective immunity beyond just antibodies.

Targeting lipid nanoparticles to the blood-brain barrier to ameliorate acute ischemic stroke.

Effective delivery of mRNA or small molecule drugs to the brain is a significant challenge in developing treatment for acute ischemic stroke (AIS). To address the problem, we have developed targeted nanomedicine to increase drug concentrations in endothelial cells of the blood-brain barrier (BBB) of the injured brain. Inflammation during ischemic stroke causes continuous neuronal death and an increase in the infarct volume. To enable targeted delivery to the inflamed BBB, we conjugated lipid nanocarriers (NCs) with antibodies that bind cell adhesion molecules expressed at the BBB. In the transient middle cerebral artery occlusion mouse model, NCs targeted to vascular cellular adhesion molecule-1 (VCAM) achieved the highest level of brain delivery, nearly two orders of magnitude higher than untargeted ones. VCAM-targeted lipid nanoparticles with luciferase-encoding mRNA and Cre-recombinase showed selective expression in the ischemic brain. Anti-inflammatory drugs administered intravenously after ischemic stroke reduced cerebral infarct volume by 62% (interleukin-10 mRNA) or 35% (dexamethasone) only when they were encapsulated in VCAM-targeted NCs. Thus, VCAM-targeted lipid NCs represent a new platform for strongly concentrating drugs within the compromised BBB of penumbra, thereby ameliorating AIS.

Association between oral and fecal microbiome dysbiosis and treatment complications in pediatric patients undergoing allogeneic hematopoietic stem cell transplantation.

The oral and gastrointestinal mucosae represent the main targets of the toxic effect of chemo and/or radiotherapy administered during the conditioning regimen before hematopoietic stem cell transplant (HSCT). These harmful consequences and the immunological complications that may occur after the transplant (such as Graft versus Host Disease, GvHD) are responsible for the clinical symptoms associated with mucositis during the aplasia phase, like pain, nausea, vomiting, and diarrhea. These toxicities could play a critical role in the oral and gastrointestinal microbiomes during the post-transplant phase, and the degree of microbial dysbiosis and dysregulation among different bacterial species could also be crucial in intestinal mucosa homeostasis, altering the host's innate and adaptive immune responses and favoring abnormal immune responses responsible for the occurrence of GvHD. This prospective pediatric study aims to analyze longitudinally oral and gut microbiomes in 17 pediatric patients who received allogeneic HSCT for malignant and non-malignant diseases. The oral mucositis was mainly associated with an increased relative abundance of Fusobacteria, and Prevotella species, while Streptococcus descendants showed a negative correlation. The fecal microbiome of subjects affected by cutaneous acute GvHD (aGvHD) correlated with Proteobacteria. Oral mucosal microbiota undergoes changes after HSCT, Fusobacteria, and Prevotella represent bacterial species associated with mucositis and they could be the target for future therapeutic approaches, while fecal microbiome in patients with acute GvHD (aGvHD) revealed an increase of different class of Proteobacteria (Alphaproteobacteria and Deltaproteobacteria) and a negative correlation with the class of Gammaproteobacteria.

Physicochemical Targeting of Lipid Nanoparticles to the Lungs Induces Clotting: Mechanisms and Solutions.

Lipid nanoparticles (LNPs) have become the dominant drug delivery technology in industry, holding the promise to deliver RNA to up or down-regulate any protein of interest. LNPs have mostly been targeted to specific cell types or organs by physicochemical targeting in which LNP's lipid compositions are adjusted to find mixtures with the desired tropism. Here lung-tropic LNPs are examined, whose organ tropism derives from containing either a cationic or ionizable lipid conferring a positive zeta potential. Surprisingly, these LNPs are found to induce massive thrombosis. Such thrombosis is shown in the lungs and other organs, and it is shown that it is greatly exacerbated by pre-existing inflammation. This clotting is induced by a variety of formulations with cationic lipids, including LNPs and non-LNP nanoparticles, and even by lung-tropic ionizable lipids that do not have a permanent cationic charge. The mechanism depends on the LNPs binding to and then changing the conformation of fibrinogen, which then activates platelets and thrombin. Based on these mechanisms, multiple solutions are engineered that enable positively charged LNPs to target the lungs while ameliorating thrombosis. The findings illustrate how physicochemical targeting approaches must be investigated early for risks and re-engineered with a careful understanding of biological mechanisms.

Association of COVID-19 pandemic societal closures with gestational weight gain among women in South Carolina, 2018-2021.

PURPOSE: During the early COVID-19 pandemic, an increase in weight gain among the general population was observed; however, gestational weight gain (GWG) was not thoroughly evaluated. We evaluated changes in GWG during the pandemic closures in South Carolina. METHODS: We used live, singleton birth records to compare GWG outcomes among three pregnancy groups occurring before (January 2018-February 2020), during (March-May 2020), and after (June 2020-December 2021) pandemic closures. GWG categories were defined by the Institute of Medicine (IOM) recommendations. We used multinomial logistic regression models to calculate prevalence ratios (PRs) of GWG categories stratified by prepregnancy body mass index (BMI) category. RESULTS: We analyzed 177,571 birth records. Women with normal weight (n = 64,491, 36%) had a slightly lower prevalence of excessive GWG during and after the pandemic closures (PR 0.94; 95% CI: 0.91-0.98 and PR 0.95; 95% CI: 0.93-0.98, respectively). We observed no changes in GWG patterns for women with overweight and obesity. CONCLUSIONS: We found limited changes in GWG patterns for a subset of pregnant women during and after pandemic closures, compared with prepandemic period in South Carolina, countering findings of weight changes among the general population.

Surgical and functional outcomes of Dorsal Inlay Graft urethroplasty in revision vs primary hypospadias repair in the pediatric age.

INTRODUCTION: Over the years, Dorsal Inlay Graft (DIG) urethroplasty has gained worldwide acceptance for primary hypospadias repair. However, its safety and effectiveness for revision surgery are yet to be proven. OBJECTIVE: The aim of the study is to assess and compare complication rates and functional outcomes of DIG surgery in revision versus primary hypospadias repair. MATERIAL AND METHODS: We carried out a retrospective analysis of data collected from 53 consecutive DIG urethroplasties performed by a single surgeon at our institution. Patients were stratified in two groups - primary repair and redo-urethroplasty. For each group, we recorded standard pre-operative characteristics, surgical technicalities, complication rates and uroflowmetry parameters. RESULTS: Out of 53 DIG urethroplasties, 21 (39.6 %) where primary and 32 (60.4 %) were re-do. As expected, the two groups differed for median age at surgery: 20 months for primary and 68.5 months for revision surgery (p < 0.001). Additionally, all 21 (100 %) primary interventions were performed with a preputial graft, whereas among revision DIG urethroplasties only 2 (6.3 %) where preputial and 30 (93.8 %) were buccal (p < 0.001). Catheterization time (7 vs 8 days, p = 0.155) and postoperative complication rates (14.3 % vs 9.4 %, p = 0.581) were comparable between the primary and revision surgery group, respectively (all p > .05). Forty-two of the 53 patients underwent uroflowmetry during follow-up. Of these, 19 (63 %) patients presented with abnormal uroflowmetry and 11 (37 %) had equivocal parameters with no difference between the two groups. DISCUSSION: Dorsal Inlay Graft urethroplasty has long been known to be safe and effective for primary hypospadias repair. On the other hand, data on dorsal inlay graft urethroplasty as a salvage surgery after primary hypospadias repair failure is scarce. Surprisingly, according to our findings, surgical outcomes and complication rates are comparable between primary and revision hypospadias cases. Additionally, our results in the redo group are absolutely encouraging if compared to those reported in the literature for the same subset of patients. CONCLUSIONS: According to our findings, DIG urethroplasty is a safe and effective option to treat revision hypospadias repair.

Identification of Large Adenovirus Infection Outbreak at University by Multipathogen Testing, South Carolina, USA, 2022.

Using multipathogen PCR testing, we identified 195 students with adenovirus type 4 infections on a university campus in South Carolina, USA, during January-May 2022. We co-detected other respiratory viruses in 43 (22%) students. Continued surveillance of circulating viruses is needed to prevent virus infection outbreaks in congregate communities.

Protein Compartments Modulate Fibrillar Self-Assembly.

A notable feature of complex cellular environments is protein-rich compartments that are formed via liquid-liquid phase separation. Recent studies have shown that these biomolecular condensates can play both promoting and inhibitory roles in fibrillar protein self-assembly, a process that is linked to Alzheimer's, Parkinson's, Huntington's, and various prion diseases. Yet, the exact regulatory role of these condensates in protein aggregation remains unknown. By employing microfluidics to create artificial protein compartments, the self-assembly behavior of the fibrillar protein lysozyme within them can be characterized. It is observed that the volumetric parameters of protein-rich compartments can change the kinetics of protein self-assembly. Depending on the change in compartment parameters, the lysozyme fibrillation process either accelerated or decelerated. Furthermore, the results confirm that the volumetric parameters govern not only the nucleation and growth phases of the fibrillar aggregates but also affect the crosstalk between the protein-rich and protein-poor phases. The appearance of phase-separated compartments in the vicinity of natively folded protein complexes triggers their abrupt percolation into the compartments' core and further accelerates protein aggregation. Overall, the results of the study shed more light on the complex behavior and functions of protein-rich phases and, importantly, on their interaction with the surrounding environment.

Linear Ion Trap Mass Spectrometer (LITMS) Instrument Field and Laboratory Tests as Part of the ARADS Field Campaigns.

The highly compact Linear Ion Trap Mass Spectrometer (LITMS), developed at NASA Goddard Space Flight Center, combines Mars-ambient laser desorption-mass spectrometry (LD-MS) and pyrolysis-gas chromatography-mass spectrometry (GC-MS) through a single, miniaturized linear ion trap mass analyzer. The LITMS instrument is based on the Mars Organic Molecule Analyser (MOMA) investigation developed for the European Space Agency's ExoMars Rover Mission with further enhanced analytical features such as dual polarity ion detection and a dual frequency RF (radio frequency) power supply allowing for an increased mass range. The LITMS brassboard prototype underwent an extensive repackaging effort to produce a highly compact system for terrestrial field testing, allowing for molecular sample analysis in rugged planetary analog environments outside the laboratory. The LITMS instrument was successfully field tested in the Mars analog environment of the Atacama Desert in 2019 as part of the Atacama Rover Astrobiology Drilling Studies (ARADS) project, providing the first in situ planetary analog analysis for a high-fidelity, flight-like ion trap mass spectrometer. LITMS continued to serve as a laboratory tool for continued analysis of natural Atacama samples provided by the subsequent 2019 ARADS final field campaign.

Small transcriptional differences among cell clones lead to distinct NF-κB dynamics.

Transcription factor dynamics is fundamental to determine the activation of accurate transcriptional programs and yet is heterogeneous at a single-cell level, even within homogeneous populations. We asked how such heterogeneity emerges for the nuclear factor κB (NF-κB). We found that clonal populations of immortalized fibroblasts derived from a single mouse embryo display robustly distinct NF-κB dynamics upon tumor necrosis factor ɑ (TNF-ɑ) stimulation including persistent, oscillatory, and weak activation, giving rise to differences in the transcription of its targets. By combining transcriptomics and simulations we show how less than two-fold differences in the expression levels of genes coding for key proteins of the signaling cascade and feedback system are predictive of the differences of the NF-κB dynamic response of the clones to TNF-ɑ and IL-1ß. We propose that small transcriptional differences in the regulatory circuit of a transcription factor can lead to distinct signaling dynamics in cells within homogeneous cell populations and among different cell types.

Stochastic chain termination in bacterial pilus assembly.

Adhesive type 1 pili from uropathogenic Escherichia coli strains are filamentous, supramolecular protein complexes consisting of a short tip fibrillum and a long, helical rod formed by up to several thousand copies of the major pilus subunit FimA. Here, we reconstituted the entire type 1 pilus rod assembly reaction in vitro, using all constituent protein subunits in the presence of the assembly platform FimD, and identified the so-far uncharacterized subunit FimI as an irreversible assembly terminator. We provide a complete, quantitative model of pilus rod assembly kinetics based on the measured rate constants of FimD-catalyzed subunit incorporation. The model reliably predicts the length distribution of assembled pilus rods as a function of the ratio between FimI and the main pilus subunit FimA and is fully consistent with the length distribution of membrane-anchored pili assembled in vivo. The results show that the natural length distribution of adhesive pili formed via the chaperone-usher pathway results from a stochastic chain termination reaction. In addition, we demonstrate that FimI contributes to anchoring the pilus to the outer membrane and report the crystal structures of (i) FimI in complex with the assembly chaperone FimC, (ii) the FimI-FimC complex bound to the N-terminal domain of FimD, and (iii) a ternary complex between FimI, FimA and FimC that provides structural insights on pilus assembly termination and pilus anchoring by FimI.