Genome-wide association study on 13 167 individuals identifies regulators of blood CD34+cell levels.

Stem cell transplantation is a cornerstone in the treatment of blood malignancies. The most common method to harvest stem cells for transplantation is by leukapheresis, requiring mobilization of CD34+ hematopoietic stem and progenitor cells (HSPCs) from the bone marrow into the blood. Identifying the genetic factors that control blood CD34+ cell levels could reveal new drug targets for HSPC mobilization. Here we report the first large-scale, genome-wide association study on blood CD34+ cell levels. Across 13 167 individuals, we identify 9 significant and 2 suggestive associations, accounted for by 8 loci (PPM1H, CXCR4, ENO1-RERE, ITGA9, ARHGAP45, CEBPA, TERT, and MYC). Notably, 4 of the identified associations map to CXCR4, showing that bona fide regulators of blood CD34+ cell levels can be identified through genetic variation. Further, the most significant association maps to PPM1H, encoding a serine/threonine phosphatase never previously implicated in HSPC biology. PPM1H is expressed in HSPCs, and the allele that confers higher blood CD34+ cell levels downregulates PPM1H. Through functional fine-mapping, we find that this downregulation is caused by the variant rs772557-A, which abrogates an MYB transcription factor-binding site in PPM1H intron 1 that is active in specific HSPC subpopulations, including hematopoietic stem cells, and interacts with the promoter by chromatin looping. Furthermore, PPM1H knockdown increases the proportion of CD34+ and CD34+90+ cells in cord blood assays. Our results provide the first large-scale analysis of the genetic architecture of blood CD34+ cell levels and warrant further investigation of PPM1H as a potential inhibition target for stem cell mobilization.

Tracking colloidal silica particles to evaluate their dispersion and interactions in concentrated suspensions under shear force applications.

This study aimed to characterize interactions within colloidal silica particles in their concentrated suspensions, using rheo-confocal measurements and imaging, followed by image analysis. We studied the effect of shear rate (0-500 s-1) and solution pH (6, 10) on the dispersion degree of colloidal silica particles via the determination and comparison of interparticle distances and their modeling. Images corresponding to different shear rates were analyzed to identify the coordinates of the particles. These coordinates were further analyzed to calculate the distance among the particles and then their surface-to-surface distance normalized by the particle diameter (H/D). It was found that the population of the particles per unit area of the image and H/D varied with increasing shear rate. The comparison between experimentally measured and theoretically calculated H/D identified that for some particles, the former was shorter than the latter, indicating the unexpected attractions among them against the Derjaguin-Landau-Verwey-Overbeek (DLVO) theory. Then, the modification of previously reported equations for H/D was suggested and confirmed its validity. Assuming pair potential interaction and hydrodynamic interaction were the main non-DLVO interactions, their magnitudes were calculated and confirmed the significance of pH and shear application strength on particle dispersion/coagulation.

Organic waste-to-bioplastics: Conversion with eco-friendly technologies and approaches for sustainable environment.

Petrochemical-based synthetic plastics poses a threat to humans, wildlife, marine life and the environment. Given the magnitude of eventual depletion of petrochemical sources and global environmental pollution caused by the manufacturing of synthetic plastics such as polyethylene (PET) and polypropylene (PP), it is essential to develop and adopt biopolymers as an environment friendly and cost-effective alternative to synthetic plastics. Research into bioplastics has been gaining traction as a way to create a more sustainable and eco-friendlier environment with a reduced environmental impact. Biodegradable bioplastics can have the same characteristics as traditional plastics while also offering additional benefits due to their low carbon footprint. Therefore, using organic waste from biological origin for bioplastic production not only reduces our reliance on edible feedstock but can also effectively assist with solid waste management. This review aims at providing an in-depth overview on recent developments in bioplastic-producing microorganisms, production procedures from various organic wastes using either pure or mixed microbial cultures (MMCs), microalgae, and chemical extraction methods. Low production yield and production costs are still the major bottlenecks to their deployment at industrial and commercial scale. However, their production and commercialization pose a significant challenge despite such potential. The major constraints are their production in small quantity, poor mechanical strength, lack of facilities and costly feed for industrial-scale production. This review further explores several methods for producing bioplastics with the aim of encouraging researchers and investors to explore ways to utilize these renewable resources in order to commercialize degradable bioplastics. Challenges, future prospects and Life cycle assessment of bioplastics are also highlighted. Utilizing a variety of bioplastics obtained from renewable and cost-effective sources (e.g., organic waste, agro-industrial waste, or microalgae) and determining the pertinent end-of-life option (e.g., composting or anaerobic digestion) may lead towards the right direction that assures the sustainable production of bioplastics.

Advancements in sustainable production of biofuel by microalgae: Recent insights and future directions.

Microalgae is considered as sustainable and viable feedstock for biofuel production due to its significant advantages over terrestrial plants. Algal biofuels have received significant attention among researchers and energy experts owing to an upsurge in global energy issues emanating from depletion in fossil fuel reserves increasing greenhouse gases emission conflict among agricultural crops, traditional biomass feedstock, and potential futuristic energy security. Further, the exploration of value-added microalgae as sustainable and viable feedstock for the production of variety of biofuels such as biogas, bio-hydrogen, bioethanol, and biodiesel are addressed. Moreover, the assessment of life-cycle, energy balance, and environmental impacts of biofuel production from microalgae are briefly discussed. The present study focused on recent advancements in synthetic biology, metabolic engineering tools, algal bio refinery, and the optimization of algae growth conditions. This paper also elucidates the function of microalgae as bio refineries, the conditions of algae-based cultures, and other operational factors that must be adjusted to produce biofuels that are price-competitive with fossil fuels.

Generation of dysbiotic microbiota in cutaneous leishmaniasis and enhancement of skin inflammation.

Cutaneous Leishmaniasis (CL) affects millions of people globally and has a significant impact on morbidity and mortality. Innate immune mediators are likely to influence the clinical phenotype of CL through primary responses that restrict or facilitate parasite spread. The aim of this preliminary study was to bring to attention the significance of microbiota in the development of CL and emphasized the necessity of including the role of microbiota in CL while promoting a One Health approach for managing diseases. To achieve this, we used 16S amplicon metagenome sequencing and QIIME2 pipeline to analyze the microbiome composition of CL-infected patients compared to non-infected, healthy subjects. 16S sequencing analysis showed serum microbiome was dominated by Firmicutes, Proteobacteria, Bacteroidota, and Actinobacteria. CL-infected individuals, Proteobacteria were the most prevalent (27.63 ± 9.79), with the relative abundance (10.73 ± 5.33) of Proteobacteria in control. Bacilli class was found to be the most prevalent in healthy controls (30.71 ± 8.44) while (20.57 ± 9.51) in CL-infected individuals. The class Alphaproteobacteria was found to be more in CL-infected individuals (5.47 ± 2.07) as compared to healthy controls (1.85 ± 0.39). The CL-infected individuals had a significantly lower relative abundance of the Clostridia class (p < 0.0001). An altered serum microbiome of CL infection and higher microbial abundance in the serum of healthy individuals was observed.

Combined efficacy of Cinnamomum zeylanicum and doxorubicin against leukemia through regulation of TRAIL and NF-kappa B pathways in rat model.

BACKGROUND: Recent discoveries in cancer therapeutics have proven combination therapies more effective than individual drugs. This study describes the efficacy of the combination of Cinnamomum zeylanicum and doxorubicin against benzene-induced leukemia. METHODS AND RESULTS: Brine shrimp assay was used to assess the cytotoxicity of C. zeylanicum, doxorubicin and their combination. After AML induction in Sprague Dawley rats, the same drugs were given to rat groups. Changes in organ weight, haematological profile, and hepatic enzymes were determined. Real-time PCR was used to elucidate the effect on the expression of STMN1, GAPDH, P53 and various TRAIL and NF-kappaB components. C. zeylanicum reduced the cytotoxicity of doxorubicin. The combination treatment showed better anti-leukemic results than any of the individual drugs as evident from STMN1 expression (p < 0.001). It was particularly effective in reducing total white blood cell counts and recovering lymphocytes, monocytes and eosinophils along with hepatic enzymes ALT and AST (p < 0.001). All doses recovered relative organ weights and improved blood parameters. The combination therapy was particularly effective in inducing apoptosis, inhibition of proliferation marker GAPDH (p < 0.001) and NF-kappaB pathway components Rel-A (p < 0.001) and Rel-B (p < 0.01). Expressions of TRAIL components c-FLIP (p < 0.001), TRAIL ligand (p < 0.001) and caspase 8 (p < 0.01) were also altered. CONCLUSION: Cinnamomum zeylanicum in combination with doxorubicin helps to counter benzene-induced cellular and hepatic toxicity and improves haematological profile. The anti-leukemic effects are potentially due to inhibition of GAPDH and NF-kappa B pathway, and through regulation of TRAIL pathway. Our data suggests the use of C. zeylanicum with doxorubicin to improve anti-leukemic therapeutic regimes.

Comparative analysis of the serum microbiome of HIV infected individuals.

HIV infects the CD4 cells which marks the suppression of our immune system. DNA from serum of healthy, treated and untreated HIV infected individuals was extracted. The DNA was subjected to 16S metagenomic sequencing and analyzed using QIIME2 pipeline. 16S sequencing analysis showed serum microbiome was dominated by Firmicutes, Proteobacteria, Bacteroidota and Actinobacteria. Treated HIV infection showed highest abundance of Firmicutes (66.40%) significantly higher than untreated HIV infection (35.88%) and control (41.89%). Bacilli was most abundant class in treated (63.59%) and second most abundant in untreated (34.53%) while control group showed highest abundance of class Gamma-proteobacteria (45.86%). Untreated HIV infection group showed Enterococcus (10.72%) and Streptococcus (6.599%) as the most abundant species. Untreated HIV infection showed significantly higher (p = 0.0039) species richness than treated and control groups. An altered serum microbiome of treated HIV infection and higher microbial abundance in serum of untreated HIV infection was observed.

Convergence Analysis of Path Planning of Multi-UAVs Using Max-Min Ant Colony Optimization Approach.

Unmanned Aerial Vehicles (UAVs) seem to be the most efficient way of achieving the intended aerial tasks, according to recent improvements. Various researchers from across the world have studied a variety of UAV formations and path planning methodologies. However, when unexpected obstacles arise during a collective flight, path planning might get complicated. The study needs to employ hybrid algorithms of bio-inspired computations to address path planning issues with more stability and speed. In this article, two hybrid models of Ant Colony Optimization were compared with respect to convergence time, i.e., the Max-Min Ant Colony Optimization approach in conjunction with the Differential Evolution and Cauchy mutation operators. Each algorithm was run on a UAV and traveled a predetermined path to evaluate its approach. In terms of the route taken and convergence time, the simulation results suggest that the MMACO-DE technique outperforms the MMACO-CM approach.

Association of cell free mitochondrial DNA and caspase-1 expression with disease severity and ARTs efficacy in HIV infection.

HIV infection is a global health concern. Current HIV-diagnostics provide information about the disease progression and efficacy of anti-retroviral therapies (ARVs), but this information is very limited and sometimes imprecise. Present study assessed the potential role of mononuclear cell (MNC) death, expression of caspases (1&3) and cell free mitochondrial DNA (CF mt-DNA) in HIV infected individuals. Apoptosis, cell-count, expression of caspases and CF mt-DNA were measured through flow cytometry and qPCR, respectively, in HIV infected individuals (n = 120) divided in two groups i.e. ARVs-receiving (treated, n = 87), ART-naïve (untreated, n = 37) and healthy individuals (n = 47). Data showed significant (p < 0.0001) cell death in untreated individuals than treated and healthy individuals. CD4-positive T-cell percentage declined (p < 0.0001) in untreated as compared to treated individuals. Caspase-1, an indicator of pyroptosis, and CF mt-DNA were also elevated in untreated HIV infected individuals. Untreated individuals when administered with ARVs showed improved CD4-positive T-cell percentage, lower caspase-1, CF mt-DNA and cell death. Data elucidated positive co-relation between cell death and CF mt-DNA in treated and untreated HIV infected individuals. While CD4-positive T-cell percentage was negatively correlated with caspase-1 expression and CF mt-DNA. Elevated levels of CF mt-DNA and caspase-1 in HIV infected individuals, positive correlation between cell death and CF mt-DNA, negative correlation of CD4-positive T-cell percentage with CF mt-DNA and caspase-1 expression clearly indicated the potential of CF mt-DNA and caspase-1 as a novel disease progression and ARTs effectiveness biomarkers in HIV.

Chloroplast genome sequences of Artemisia maritima and Artemisia absinthium: Comparative analyses, mutational hotspots in genus Artemisia and phylogeny in family Asteraceae.

Artemisia L. is a complex genus of medicinal importance. Publicly available chloroplast genomes of few Artemisia species are insufficient to resolve taxonomic discrepancies at species level. We report chloroplast genome sequences of two further Artemisia species: A. maritima (151,061 bp) and A. absinthium (151,193 bp). Both genomes possess typical quadripartite structure comprising of a large single copy, a small single copy and a pair of long inverted repeats. The two genomes exhibited high similarities in genome sizes, gene synteny, GC content, synonymous and non-synonymous substitutions, codon usage, amino acids frequencies, RNA editing sites, microsatellites, and oligonucleotide repeats. Transition to transversion ratio was <1. Maximum likelihood tree showed Artemisia a monophyletic genus, sister to genus Chrysanthemum. We also identified 20 highly polymorphic regions including rpoC2-rps2, trnR-UCU-trnG-UCC, rps18-rpl20, and trnL-UAG-rpl32 that could be used to develop authentic and cost-effective markers to resolve taxonomic discrepancies and infer phylogenetic relationships among Artemisia species.

Collective Motion and Self-Organization of a Swarm of UAVs: A Cluster-Based Architecture.

This study proposes a collective motion and self-organization control of a swarm of 10 UAVs, which are divided into two clusters of five agents each. A cluster is a group of UAVs in a dedicated area and multiple clusters make a swarm. This paper designs the 3D model of the whole environment by applying graph theory. To address the aforesaid issues, this paper designs a hybrid meta-heuristic algorithm by merging the particle swarm optimization (PSO) with the multi-agent system (MAS). First, PSO only provides the best agents of a cluster. Afterward, MAS helps to assign the best agent as the leader of the nth cluster. Moreover, the leader can find the optimal path for each cluster. Initially, each cluster contains agents at random positions. Later, the clusters form a formation by implementing PSO with the MAS model. This helps in coordinating the agents inside the nth cluster. However, when two clusters combine and make a swarm in a dynamic environment, MAS alone is not able to fill the communication gap of n clusters. This study does it by applying the Vicsek-based MAS connectivity and synchronization model along with dynamic leader selection ability. Moreover, this research uses a B-spline curve based on simple waypoint defined graph theory to create the flying formations of each cluster and the swarm. Lastly, this article compares the designed algorithm with the NSGA-II model to show that the proposed model has better convergence and durability, both in the individual clusters and inside the greater swarm.

Compact ultrabroad-bandwidth cascaded arrayed waveguide gratings.

Here, we present a compact, high-resolution, and ultrabroad-bandwidth arrayed waveguide grating (AWG) realized in a silicon nitride (Si3N4) platform. The AWG has a cascaded configuration with a 1×3 flat-passband AWG as the primary filter and three 1×70 AWGs as secondary filters (i.e. 210 output channels in total). The primary AWG has 0.5-dB bandwidth of 45 nm over 190 nm spectral range. The ultrabroad-bandwidth is achieved by using an innovative design that is based on a multiple-input multi-mode interference (MMI) coupler placed at the entrance of the first free propagation region of the primary AWG. The optical bandwidth of the cascaded AWG is 190 nm, and the spectral resolution is 1 nm. The overall device size is only 1.1 × 1.0 cm2. Optical loss at the central channel is 4 dB, which is 3 dB less than a conventional design with the same bandwidth and resolution values but using a primary filter with Gaussian transfer function. To the best of our knowledge, this is the first demonstration of an ultrabroad-bandwidth cascaded AWG on a small footprint. We also propose a novel low-loss (∼ 0.8 dB) design using a small AWG instead of an MMI coupler in the primary filter part, which can be used in applications where the light intensity is very weak, such as Raman spectroscopy.

Assessment of cell free mitochondrial DNA as a biomarker of disease severity in different viral infections.

OBJECTIVE: Cell Free mitochondrial DNA (CF mt-DNA) has emerged as a novel biomarker to investigate disease pathophysiology of different infections. The present study was designed to elucidate the association between CF mt-DNA, IL-6 and viral load in HIV, HBV and HCV infections and predict its role as a potential biomarker to assess the disease severity in viral infections. METHODS: Total 120 blood samples were collected from January 2018 to December 2018 of HIV, HBV and HCV patients and healthy controls (30 samples in each group). DNA and RNA were extracted from the serum to determine the levels of CF mt-DNA and viral load, respectively. IL-6 from the serum of infected individuals was quantified with ELISA. RESULTS: HCV patients showed the highest levels of CF mt-DNA, IL-6 and viral load, followed by HBV and HIV. Significant correlation was found between CF mt-DNA and IL-6 among the HBV patients (p=0.017). However, no significant correlation of CF mt-DNA was observed with IL-6 in HIV and HCV or with the viral load in any of the three infections. CONCLUSION: Elevated CF mt-DNA indicates its role in severity of viral infections. Independence of CF mt-DNA expression from viral load and IL-6 in case of HIV and HCV suggests involvement of other inflammatory pathways regulating CF mt-DNA elevation.

Fuzzy-Based Hybrid Control Algorithm for the Stabilization of a Tri-Rotor UAV.

In this paper, a new and novel mathematical fuzzy hybrid scheme is proposed for the stabilization of a tri-rotor unmanned aerial vehicle (UAV). The fuzzy hybrid scheme consists of a fuzzy logic controller, regulation pole-placement tracking (RST) controller with model reference adaptive control (MRAC), in which adaptive gains of the RST controller are being fine-tuned by a fuzzy logic controller. Brushless direct current (BLDC) motors are installed in the triangular frame of the tri-rotor UAV, which helps maintain control on its motion and different altitude and attitude changes, similar to rotorcrafts. MRAC-based MIT rule is proposed for system stability. Moreover, the proposed hybrid controller with nonlinear flight dynamics is shown in the presence of translational and rotational velocity components. The performance of the proposed algorithm is demonstrated via MATLAB simulations, in which the proposed fuzzy hybrid controller is compared with the existing adaptive RST controller. It shows that our proposed algorithm has better transient performance with zero steady-state error, and fast convergence towards stability.

Triple-Vessel Disease in a High-Risk Surgical Patient Treated With Nine Drug-Eluting Stents.

Coronary artery disease (CAD) is a major cause of morbidity and mortality in the United States, and as strides have been made in its management, outcomes have continued to improve. Management has evolved from expectant management to coronary artery bypass graft surgery and thrombolysis, to more recently percutaneous intervention with stenting and medical management in select cases. Here, we describe a case of a complex patient with severe triple-vessel disease who was deemed a poor surgical candidate for coronary artery bypass graft surgery and would instead undergo high-risk percutaneous intervention with the placement of nine drug-eluting stents.

PR prolongation as a predictor of atrial fibrillation onset: A state-of-the-art review.

First-degree atrioventricular block (1-AVB), characterized by a PR interval exceeding 200 milliseconds, has traditionally been perceived as a benign cardiac condition. Recently, this perception has been challenged by investigations that indicate a potential association between PR prolongation and an elevated risk of atrial fibrillation (AF). To consolidate these findings, we performed a comprehensive review to assess the available evidence indicating a relationship between these two conditions. We searched MEDLINE and EMBASE databases as well as manually searched references of retrieved articles. We selected 18 cohort studies/meta-analyses involving general and special populations. Consistent findings across expansive cohort studies reveal that incremental increases in the PR interval may serve as an independent risk factor for AF. However, our analyses underscore the need for further research into the association between 1-AVB, defined by a specified PR interval cutoff, and the risk of AF.

Advancing acute MI care in densely populated low- and middle-income countries (LMICs): innovative stand-alone chest pain units for expedited triage and timely management.

Background: The incidence of myocardial infarction (MI) and its adverse effects on health and mortality remain high in densely populated low- and middle-income countries (LMICs). To address the issue of densely populated areas and timely access to primary PCI, chest pain units (CPUs) were deployed at strategic locations in Karachi, with a populace of over 23 million people. This study describes the results of this initiative in expediting MI care. Methods: Between 2017 and 2023, 18 CPUs, each with a cardiologist, technician, ECG machine, crash cart and an ambulance were placed in high density areas. Findings: A total of 915,564 patients were seen at 18 CPUs over the study period. 692,444 (75.6%) were categorized as non-cardiac and subsequently discharged. 223,120 (24.6%) patients were directed for additional care. Of these, 9% had ST elevation myocardial infarction (STEMI) (19, 580), 29% NSTE ACS/Unstable angina, and 31% with various other cardiac conditions. Additionally, 31% were referred for medical outpatient evaluation. CPU inception led to a significant annual growth (16-20%) in primary PCI procedures at NICVD, totaling 20,000 by 2022-2023. The median first medical contact to device time was 100 min (IQR 80-135), while total ischemic was 232 min (IQR: 172-315; 5th -95th %le: 50-920). The overall in-hospital mortality rate for patients undergoing primary PCI was 5.58%, with a range between 5.1% and 6.9% through the study period. Interpretation: Novel standalone chest pain units, operational from 2017 in Karachi, Pakistan, have expedited triage and enhanced the timely management of AMI. This initiative's transformative impact presents a model that resonates beyond borders, serving as a role model for global healthcare systems. Funding: The CPU and primary PCI program is fully funded by the government of Sindh. No specific funding was allocated for this study.

Deciphering the genetics and mechanisms of predisposition to multiple myeloma.

Multiple myeloma (MM) is an incurable malignancy of plasma cells. Epidemiological studies indicate a substantial heritable component, but the underlying mechanisms remain unclear. Here, in a genome-wide association study totaling 10,906 cases and 366,221 controls, we identify 35 MM risk loci, 12 of which are novel. Through functional fine-mapping and Mendelian randomization, we uncover two causal mechanisms for inherited MM risk: longer telomeres; and elevated levels of B-cell maturation antigen (BCMA) and interleukin-5 receptor alpha (IL5RA) in plasma. The largest increase in BCMA and IL5RA levels is mediated by the risk variant rs34562254-A at TNFRSF13B. While individuals with loss-of-function variants in TNFRSF13B develop B-cell immunodeficiency, rs34562254-A exerts a gain-of-function effect, increasing MM risk through amplified B-cell responses. Our results represent an analysis of genetic MM predisposition, highlighting causal mechanisms contributing to MM development.