Search

Polyamines are abundant and evolutionarily conserved metabolites that are essential for life. Dietary polyamine supplementation extends life-span and health-span. Dysregulation of polyamine homeostasis is linked to Parkinson's disease and cancer, driving interest in therapeutically targeting this pathway. However, measuring cellular polyamine levels, which vary across cell types and states, remains challenging. We introduce a first-in-class genetically encoded polyamine reporter for real-time measurement of polyamine concentrations in single living cells. This reporter utilizes the polyamine-responsive ribosomal frameshift motif from the OAZ1 gene. We demonstrate broad applicability of this approach and reveal dynamic changes in polyamine levels in response to genetic and pharmacological perturbations. Using this reporter, we conducted a genome-wide CRISPR screen and uncovered an unexpected link between mitochondrial respiration and polyamine import, which are both risk factors for Parkinson's disease. By offering a new lens to examine polyamine biology, this reporter may advance our understanding of these ubiquitous metabolites and accelerate therapy development. .

Unlike second-generation tyrosine kinase inhibitors, effects of imatinib on the cardiovascular (CV) system are debatable. The current case-control study aimed to evaluate the CV effects of imatinib in patients with chronic myeloid leukemia (CML) using non-invasive 2D-echocardiography testing. Patients with CML ≥ 13 years attending the adult haematology clinic of a tertiary care hospital in north India were prospectively enrolled over 1.5 years. The study population ( n  = 110) consisted of 35 newly diagnosed patients (treatment-naïve group) and 75 patients under imatinib therapy ≥ 1 year (treated group). All the eligible patients were subjected to 2D-echocardiography to calculate pulmonary artery systolic pressure (PASP), left ventricular ejection fraction (LVEF) and deceleration time (DT). These parameters were compared between the two groups. P -value < 0.05 was considered statistically significant. The median age of study population was 40 years (range, 13-73) and M:F ratio was 1.14:1. Both the groups had similar demographics at the diagnosis including CV risk factors. The median PASP of the treated group was 2 mm Hg higher than the treatment-naïve group (25 vs 23 mm Hg, p -value = 0.919). The median LVEF of the treated group was 3.2% lower than the treatment-naïve group (58.5% vs 61.72%, p -value = 0.577). The median DT of the treated group was 7 ms shorter than treatment-naïve group (211 vs 204 ms, p -value = 0.411). Imatinib causes potential cardiac dysfunction in patients with CML. Large scale prospective follow-up trials in the same cohort of patients are needed to validate the findings of our study., Competing Interests: Competing InterestsNone., (© Indian Society of Hematology and Blood Transfusion 2024. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

This work deals with the synthesis of SnO 2 -modified sugarcane bagasse biochar (SnO 2 -SBB) nanocomposites using an impregnation method. XRD, FTIR, SEM, and EDX analyses were used to characterize the produced nanocomposites. Several factors influencing the removal of malachite green from wastewater via the adsorption process were explored to maximize the effectiveness of this process. These factors included the different doses of nanocomposites, pH, temperature, contact time, etc. Studies on batch adsorption were conducted to examine the impact of operational parameters, such as contact time (5 to 30 minutes), adsorbent dosage (5 to 40 mg), pH (2 to 10), and temperature (303, 323, and 353 K), on the percentage of MG dye removal. The adsorption kinetics of MG dye over SnO 2 -SBB nanocomposites were evaluated with the aid of the Langmuir adsorption isotherm, which provided a good fit ( R 2 = 0.99) for pseudo-second-order kinetics. The thermodynamic parameters revealed spontaneous and exothermic adsorption of MG dye over SnO 2 -SBB nanocomposites. A maximum adsorption capacity ( q max ) of 52.64 ± 0.03 for 0.3 SnO 2 -SBB and 73.86 ± 0.05 for 0.5 SnO 2 -SBB nanocomposites was observed. The newly synthesized SnO 2 -SBB nanocomposites showed negative zeta potential, which facilitated the adsorption of hydrated cationic dye molecules due to the electrostatic force of attraction., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Nature uses bottom-up self-assembly to build structures with remarkable complexity and functionality. Understanding how molecular-scale interactions translate to macroscopic properties remains a major challenge and requires systems that effectively bridge these two scales. Here, we generate DNA and RNA liquids with exquisite programmability in their material properties. Nucleic acids are negatively charged, and in the presence of polycations, they may condense to a liquid-like state. Within these liquids, DNA and RNA retain sequence-specific hybridization abilities. We show that intermolecular hybridization in the condensed phase cross-links molecules and slows down chain dynamics. This reduced chain mobility is mirrored in the macroscopic properties of the condensates. Molecular diffusivity and material viscosity scale with the intermolecular hybridization energy, enabling precise sequence-based modulation of condensate properties over orders of magnitude. Our work offers a robust platform to create self-assembling programmable fluids and may help advance our understanding of liquid-like compartments in cells.

This study investigates the use of carbonized Himalayan Chir Pine Biomass, known as Chir Pine Activated Carbon (CPAC), as an eco-friendly and cost-effective adsorbent for efficient industrial dye removal, with a focus on environmental sustainability. By applying different additive treatments, four adsorbents (C1, C2, C3, and C4) were formulated. CPAC was synthesized through pyrolysis and characterized using various analytical techniques including FE-SEM, X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), and differential scanning calorimetry (DSC). The adsorption capacity of CPAC was evaluated using Malachite Green (MG) dye as a model contaminant. FE-SEM images revealed high porosity (~ 10 µm) and a high surface area (119.886 m 2 /g) as confirmed by BET testing. CPAC effectively removed MG dye within 30 min at a solution pH of 7. Langmuir and Freundlich isotherm models indicated both monolayer and multilayer adsorption, while kinetic models suggested chemisorption. The regeneration efficiency was assessed using 0.1 N HCl over five consecutive cycles, with C4 demonstrating a high regeneration tendency of 85% and only a 9% reduction in adsorption ability after the fifth cycle. The developed CPAC shows excellent potential for use in the textile, paper, and leather industries for industrial dye adsorption, contributing to the protection of aquatic ecosystems. Additionally, CPAC can be utilized in other water and air purification applications., (© 2024. The Author(s).)

Background: Immune dysregulation is crucial in the pathogenesis of acquired aplastic anaemia (aAA). There is paucity of data regarding correlation of baseline cytokine profile with treatment response in aAA., Objective: Present prospective case-control study aimed to correlate the baseline cytokines in patients with aAA with the treatment response., Methods: Fifty-one patients with newly-diagnosed aAA > 13 years of either sex were enrolled over 1.5 years. Twenty age-and sex-matched healthy controls (HC) were also included. The cytokine profile (IL-2, 4, 6, 8, 10, 17, IFN-γ and TNF-α) in the peripheral blood plasma of aAA patients was performed at the baseline using cytometric bead analysis. The cytokine levels were compared with HC and correlated with response to immunosuppressive therapy (IST) at 3-months., Results: The median age of cases was 29 years (range,13-74). The cases had higher mean levels of IL2 (p = 0.326), IL4 (p = 0.038), IL6 (p = 0.000), IL10 (p = 0.002), TNF-α (p = 0.302), IFN-γ (p = 0.569) and IL-17 (p = 0.284) than the HC. The baseline levels of all the cytokines were higher (statistically non-significant) among responders (n = 13) than the non-responders (n = 14) to IST., Conclusions: Baseline cytokine profile in patients with aAA might predict response to the IST. Larger studies are needed to validate our results., Competing Interests: Declaration of competing interest None., (Copyright © 2024. Published by Elsevier Inc.)

The Coronavirus Disease of 2019 (COVID-19) pandemic had a profound impact on colorectal cancer (CRC) screening and diagnostic testing. During the initial months of the pandemic, there was a sharp decline in colonoscopies performed as many areas were on lockdown and elective procedures could not be performed. In later months, even when routine procedures started being scheduled again, some patients became fearful of contracting COVID during colonoscopy or lost their health insurance, leading to further delays in CRC diagnosis by colonoscopy. Previous studies have reported the dramatic decrease in colonoscopy rates and CRC detection at various institutions across the country, but no previous study has been performed to determine rates of colorectal screening by colonoscopy in Hawai'i where the demographics of CRC differ. The team investigated the pandemic's impact on colonoscopy services and colorectal neoplasia detection at several large outpatient endoscopy centers in Hawai'i and also classified new CRC cases by patient demographics of age, sex, and ethnicity. There were fewer colonoscopies performed in these endoscopy centers in 2020 than in 2019 and a disproportionate decrease in CRC cases diagnosed. Elderly males as well as Native Hawaiians/Pacific Islanders were most impacted by this decrease in CRC detection. It is possible there will be an increase in later stage presentation of CRC and eventual CRC related mortality among these patients., Competing Interests: None of the authors identify a conflict of interest., (©Copyright 2024 by University Health Partners of Hawai‘i (UHP Hawai‘i).)

Background: The hypothalamus, a small yet crucial neuroanatomical structure, integrates external (e.g., environmental) and internal (e.g., physiological/hormonal) stimuli. This integration governs various physiological processes and influences cognitive, emotional, and behavioral outcomes. It serves as a functional bridge between the nervous and endocrine systems, maintaining homeostasis and coordinating bodily functions., Summary: Recent advancements in the neurobiology of the hypothalamus have elucidated its functional map, establishing a causal relationship between its responses-such as respiration, sleep, and stress-and various physiological processes. The hypothalamus facilitates and coordinates these complex processes by processing diverse stimuli, enabling the body to maintain internal balance and respond effectively to external demands. This review delves into the hypothalamus's intricate connections with cognition, emotion, and physiology, exploring how these interactions promote overall well-being and adaptability., Key Message: Targeted external stimuli can modulate hypothalamic neuronal activities, impacting the physiological, cognitive, and emotional landscape. The review highlights non-invasive techniques, such as controlled breathing exercises, optimized sleep architecture, and stress management, as potential methods to enhance hypothalamic function. Ultimately, this comprehensive review underscores the multifaceted role of the hypothalamus in integrating signals, maintaining homeostasis, and influencing cognition, emotion, and physiology., Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article., (© The Author(s) 2024.)

Objective: Drug delivery from a drug-loaded device into an adjacent tissue is a complicated process involving drug transport through diffusion and advection, coupled with drug binding kinetics responsible for drug uptake in the tissue. This work presents a theoretical model to predict drug delivery from a device into a multilayer tissue, assuming linear reversible drug binding in the tissue layers., Methods: The governing mass conservation equations based on diffusion, advection and drug binding in a multilayer cylindrical geometry are written, and solved using Laplace transformation. The model is used to understand the impact of various non-dimensional parameters on the amounts of bound and unbound drug concentrations as functions of time., Results: Good agreement for special cases considered in past work is demonstrated. The effect of forward and reverse binding reaction rates on the multilayer drug binding process is studied in detail. The effect of the nature of the external boundary condition on drug binding and drug loss is also studied. For typical parameter values, results indicate that only a small fraction of drug delivered binds in the tissue. Additionally, the amount of bound drug rises rapidly with time due to early dominance of the forward reaction, reaches a maxima and then decays due to the reverse reaction., Conclusions: The general model presented here can account for other possible effects such as drug absorption within the device. Besides generalizing past work on drug delivery modeling, this work also offers analytical tools to understand and optimize practical drug delivery devices., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Women have smaller coronary size than men independent of body surface area. Female to male heart transplantation demonstrates coronary lumen enlargement., Purpose: To investigate relationships between endogenous androgens and coronary luminal size in women with suspected ischemic heart disease (IHD)., Methods: We analyzed 69 women with available androgen levels., Results: Group mean age was 54 ± 10 years with 64 % post-menopausal. Lumen cross-sectional area (CSA) and external elastic membrane (EEM) CSA positively correlated with free testosterone (FT) ( r  = 0.29, p  = 0.049; r = 0.29, p  = 0.01), respectively, and negatively correlated with SHBG ( r  = -0.26, p  = 0.03; r  = -0.29, p  = 0.02), respectively. Atheroma CSA positively correlated with FT ( r  = 0.24. p  = 0.05). These correlations became non-significant after adjusting for waist circumference., Conclusions: In women with suspected ischemic heart disease, endogenous androgens, coronary atheroma and luminal size are related, and may be moderated by waist circumference., Competing Interests: CNBM receives consulting fees from SHL Telemedicine, and consulting and stocks from iRhythm. CJP serves as the Editor-in-Chief of AHJO., (© 2024 The Authors. Published by Elsevier Inc.)

Mutations in myocilin (MYOC) are the leading known genetic cause of primary open-angle glaucoma, responsible for about 4% of all cases. Mutations in MYOC cause a gain-of-function phenotype in which mutant myocilin accumulates in the endoplasmic reticulum (ER) leading to ER stress and trabecular meshwork (TM) cell death. Therefore, knocking out myocilin at the genome level is an ideal strategy to permanently cure the disease. We have previously utilized CRISPR/Cas9 genome editing successfully to target MYOC using adenovirus 5 (Ad5). However, Ad5 is not a suitable vector for clinical use. Here, we sought to determine the efficacy of adeno-associated viruses (AAVs) and lentiviruses (LVs) to target the TM. First, we examined the TM tropism of single-stranded (ss) and self-complimentary (sc) AAV serotypes as well as LV expressing GFP via intravitreal (IVT) and intracameral (IC) injections. We observed that LV&#95;GFP expression was more specific to the TM injected via the IVT route. IC injections of Trp-mutant scAAV2 showed a prominent expression of GFP in the TM. However, robust GFP expression was also observed in the ciliary body and retina. We next constructed lentiviral particles expressing Cas9 and guide RNA (gRNA) targeting MYOC (crMYOC) and transduction of TM cells stably expressing mutant myocilin with LV&#95;crMYOC significantly reduced myocilin accumulation and its associated chronic ER stress. A single IVT injection of LV&#95;crMYOC in Tg-MYOC Y437H mice decreased myocilin accumulation in TM and reduced elevated IOP significantly. Together, our data indicates, LV&#95;crMYOC targets MYOC gene editing in TM and rescues a mouse model of myocilin-associated glaucoma., (© 2024. The Author(s).)

Objectives: In the United States, end-stage kidney disease (ESKD) is responsible for high mortality and significant healthcare costs, with the number of cases sharply increasing in the past 2 decades. In this study, we aimed to reduce these impacts by developing an ESKD model for predicting its occurrence in a 2-year period., Materials and Methods: We developed a machine learning (ML) pipeline to test different models for the prediction of ESKD. The electronic health record was used to capture several kidney disease-related variables. Various imputation methods, feature selection, and sampling approaches were tested. We compared the performance of multiple ML models using area under the ROC curve (AUCROC), area under the Precision-Recall curve (PR-AUC), and Brier scores for discrimination, precision, and calibration, respectively. Explainability methods were applied to the final model., Results: Our best model was a gradient-boosting machine with feature selection and imputation methods as additional components. The model exhibited an AUCROC of 0.97, a PR-AUC of 0.33, and a Brier score of 0.002 on a holdout test set. A chart review analysis by expert physicians indicated clinical utility., Discussion and Conclusion: An ESKD prediction model can identify individuals at risk for ESKD and has been successfully deployed within our health system., Competing Interests: The authors declare no competing interests., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Medical Informatics Association.)

Expansions of CAG trinucleotide repeats cause several rare neurodegenerative diseases. The disease-causing repeats are translated in multiple reading frames and without an identifiable initiation codon. The molecular mechanism of this repeat-associated non-AUG (RAN) translation is not known. We find that expanded CAG repeats create new splice acceptor sites. Splicing of proximal donors to the repeats produces unexpected repeat-containing transcripts. Upon splicing, depending on the sequences surrounding the donor, CAG repeats may become embedded in AUG-initiated open reading frames. Canonical AUG-initiated translation of these aberrant RNAs may account for proteins that have been attributed to RAN translation. Disruption of the relevant splice donors or the in-frame AUG initiation codons is sufficient to abrogate RAN translation. Our findings provide a molecular explanation for the abnormal translation products observed in CAG trinucleotide repeat expansion disorders and add to the repertoire of mechanisms by which repeat expansion mutations disrupt cellular functions., Competing Interests: Declaration of interests A.J. is a member of the scientific advisory board of Molecular Cell., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Cell-free DNA (cfDNA) is a promising biomarker for disease prediction in many cancers, including acute leukemia (acute myeloid leukemia [AML] and acute lymphoblastic leukemia [ALL]). This study investigated the role of cfDNA in predicting relapse or unfavorable outcomes in acute leukemia patients upon initial diagnosis. Methods: Paired peripheral blood samples of 25 patients with ALL and AML were compared at baseline and induction/follow-up and clinically correlated with clinicopathological and outcome variables according to the risk category. cfDNA was isolated using commercial cfDNA extraction kits. The probability of poor outcomes in high-risk groups and a cut-off value for risk stratification minimal residual disease (MRD) positivity and outcome prediction were derived. Results: Twenty-five patients diagnosed with AML and ALL were risk-stratified based on NCI risk stratification, and of these 25 patients, 4 patients were of standard risk (SR) and 1 patient was of intermediate risk (IR), while a majority of patients (80%) were of high risk (HR). Of these, four HR patients passed away. The ratio of cfDNA reduction at baseline and the end of induction was a strong predictor of poor outcomes in high-risk patients, regardless of the MRD status. A cfDNA ratio score of 2.6 or higher at diagnosis/remission predicted poor outcomes, with higher accuracy than conventional MRD detection by flow cytometry. Conclusion: A higher cfDNA ratio at diagnosis/remission or at baseline predicts poor outcomes in acute leukemia patients. This pilot study suggests that cfDNA ratio scoring may be a useful tool for predicting prognosis in acute leukemia patients, regardless of the MRD status., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 George, Rishi, Singh, Vishmaya, Kumar, Kushwaha, Kaur, Bhardwaj, Jain, Jain, Chaudhry and Misra.)

Aim: To evaluate the apoptosis-inducing properties of undoped and silver-doped-zinc-oxide nanoparticles (SDZONs) synthesized using Boswellia serrata against MCF-7 (Luminal-A) and MDA-MB-231 (Triple-negative) breast cancer cell lines. Methodology: Nanostructures were developed by facile biohydrothermal method and characterized by x-ray diffraction (XRD), Fourier transform infrared (FTIR), and high resolution transmission electron microscopy (HR-TEM). The comparative effect of doping and dose concentration of nanostructures on cytotoxicity was measured using MTT and trypan-blue-exclusion assay. Results: SDZONs exhibited greater cytotoxicity (20.71%, 27.31% cell viability) as compared with undoped nanostructures (35.81%, 37.08% cell viability) against MCF 7 and MDA-MB-231, respectively. Conclusion: The activity of biogenic nanostructures was highly dependent on doping, dose, and type of cell lines used. The novel biogenic SDZONs could be exploited as a promising, cost-effective, and environmentally benign strategy to curb breast cancer.

A class of exceptionally bioactive molecules known as reactive oxygen species (ROS) have been widely studied in the context of cancer. They play a significant role in the etiopathogenesis for cancer. Implication of ROS in cancer biology is an evolving area, considering the recent advances; insights into their generation, role of genomic and epigenetic regulators for ROS, earlier thought to be a chemical process, with interrelations with cell death pathways- Apoptosis, ferroptosis, necroptosis and autophagy has been explored for newer targets that shift the balance of ROS towards cancer cell death. ROS are signal transducers that induce angiogenesis, invasion, cell migration, and proliferation at low to moderate concentrations and are considered normal by-products of a range of biological activities. Although ROS is known to exist in the oncology domain since time immemorial, its excessive quantities are known to damage organelles, membranes, lipids, proteins, and nucleic acids, resulting in cell death. In the last two decades, numerous studies have demonstrated immunotherapies and other anticancer treatments that modulate ROS levels have promising in vitro and in vivo effects. This review also explores recent targets for therapeutic interventions in cancer that are based on ROS generation or inhibition to disrupt the cell oxidative stress balance. Examples include-metabolic targets, targeted therapy with biomarkers, natural extracts and nutraceuticals and targets developed in the area of nano medicine. In this review, we present the molecular pathways which can be used to create therapy plans that target cancer by regulating ROS levels, particularly current developments and potential prospects for the effective implementation of ROS-mediated therapies in clinical settings. The recent advances in complex interaction with apoptosis especially ferroptosis and its role in epigenomics and modifications are a new paradigm, to just mechanical action of ROS, as highlighted in this review. Their inhibition by nutraceuticals and natural extracts has been a scientific challenging avenue that is explored. Also, the inhibition of generation of ROS by inhibitors, immune modulators and inhibitors of apoptosis and ferroptosis is explored in this review., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Verma, Rishi, George, Kushwaha, Dhandha, Kaur, Jain, Jain, Chaudhry, Singh, Siraj and Misra.)

Competing Interests: Competing interests: The BMJ has judged that there are no disqualifying financial ties to commercial companies. The authors declare no interests.

Competing Interests: Competing interests: The BMJ has judged that there are no disqualifying financial ties to commercial companies. The authors declare no interests.

The present study described the synthesis and characterization of MOF-76(Tb) for hydrogen storage and humidity sensing applications. The structure and morphology of as-synthesized material were studied using powder X-ray diffraction, scanning, and transmission electron microscopy. The crystal structure of MOF-76(Tb) consists of terbium(III) and benzene-1,3,5-tricarboxylate(-III) ions, one coordinated aqua ligand and one crystallization N,N´-dimethylformamide molecule. The polymeric framework of MOF-76(Tb) contains 1D sinusoidally shaped channels with sizes of 6.6 × 6.6 Å propagating along c crystallographic axis. The thermogravimetric analysis of the prepared material exhibited thermal stability up to 600 °C. At 77 K and pressure up to 20 bar; 0.6 wt.% hydrogen storage capacity for MOF-76(Tb) was observed. Finally, the humidity sensing measurements (water adsorption experiments) were performed, and the results indicate that MOF-76(Tb) is not a suitable material for moisture sensing applications., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Dissolution of drug from its solid form to a dissolved form is an important consideration in the design and optimization of drug delivery devices, particularly owing to the abundance of emerging compounds that are extremely poorly soluble. When the solid dosage form is encapsulated, for example by the porous walls of an implant, the impact of the encapsulant drug transport properties is a further confounding issue. In such a case, dissolution and diffusion work in tandem to control the release of drug. However, the interplay between these two competing processes in the context of drug delivery is not as well understood as it is for other mass transfer problems, particularly for practical controlled-release considerations such as an encapsulant layer around the drug delivery device. To address this gap, this work presents a mathematical model that describes controlled release from a drug-loaded device surrounded by a passive porous layer. A solution for the drug concentration distribution is derived using the method of eigenfunction expansion. The model is able to track the dissolution front propagation, and predict the drug release curve during the dissolution process. The utility of the model is demonstrated through comparison against experimental data representing drug release from a cylindrical drug-loaded orthopedic fixation pin, where the model is shown to capture the data very well. Analysis presented here reveals how the various geometrical and physicochemical parameters influence drug dissolution and, ultimately, the drug release profile. It is found that the non-dimensional initial concentration plays a key role in determining whether the problem is diffusion-limited or dissolution-limited, whereas the nature of the problem is largely independent of other parameters including diffusion coefficient and encapsulant thickness. We expect the model will prove to be a useful tool for those designing encapsulated drug delivery devices, in terms of optimizing the design of the device to achieve a desired drug release profile., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

In this paper, we report the effect of metal oxide (Fe 2 O 3 ) loading in different weight ratios (0.5%, 1%, 2%, and 4%) on the structural and electrical parameters, viz., the complex dielectric constant, electric modulus spectra, and the AC conductivity, of polymeric composites of PVDF/PMMA (30/70 weight ratio) blend. The structural and geometric measurements have been analyzed with the help of peak location, peak intensity, and peak shape obtained from XRD as well as from FTIR spectra. The electrical properties have been investigated using an impedance analyzer in the frequency range 100 Hz to 1 MHz. The real parts of the complex permittivity and the dielectric loss tangent of these materials are found to be frequency independent in the range from 20 KHz to 1 MHz, but they increase with the increase in the concentration of nano-Fe 2 O 3 . The conductivity also increases with an increased loading of Fe 2 O 3 in PVDF/PMMA polymer blends. The electric modulus spectra were used to analyze the relaxation processes associated with the Maxwell-Wagner-Sillars mechanism and chain segmental motion in the polymer mix.

Objectives: Diagnostic error is not uncommon and diagnostic accuracy can be improved with the use of problem representation, pre-test probability, and Bayesian analysis for improved clinical reasoning., Case Presentation: A 48-year-old female presented as a transfer from another Emergency Department (ED) to our ED with crushing, substernal pain associated with dyspnea, diaphoresis, nausea, and a tingling sensation down both arms with radiation to the back and neck. Troponins were elevated along with an abnormal electrocardiogram. A negative myocardial perfusion scan led to the patient's discharge. The patient presented to the ED 10 days later with an anterior ST-elevation myocardial infarction., Conclusions: An overemphasis on a single testing modality led to diagnostic error and a severe event. The use of pre-test probabilities guided by history-taking can lead to improved interpretation of test results, ultimately improving diagnostic accuracy and preventing serious medical errors., (© 2023 Walter de Gruyter GmbH, Berlin/Boston.)

Pathogenic repeat sequences underlie several human disorders, including amyotrophic lateral sclerosis, Huntington's disease, and myotonic dystrophy. Here, we speak to several researchers about how repeat sequences have been implicated in affecting all aspects of the Central Dogma of molecular biology through their effects on DNA, RNA, and protein., Competing Interests: Declaration of interests E.T.W. is a cofounder of and consultant to Kate Therapeutics. A.J. is a member of the scientific advisory board of Molecular Cell. P.K.T. served as a consultant to Denali Therapeutics and holds a shared patent with Ionis Pharmaceuticals. Y.N. discloses the patent PCT/JP2017/23,162 related to this work., (Copyright © 2022 Elsevier Inc. All rights reserved.)

CAG trinucleotide repeat expansions cause several neurodegenerative diseases, including Huntington's disease and spinocerebellar ataxia. RNAs with expanded CAG repeats contribute to disease in two unusual ways. First, these repeat-containing RNAs may agglomerate in the nucleus as foci that sequester several RNA-binding proteins. Second, these RNAs may undergo aberrant repeat-associated non-AUG (RAN) translation in multiple frames and produce aggregation-prone proteins. The relationship between RAN translation and RNA foci, and their relative contributions to cellular dysfunction, are unclear. Here, we show that CAG repeat-containing RNAs that undergo RAN translation first accumulate at nuclear foci and, over time, are exported to the cytoplasm. In the cytoplasm, these RNAs are initially dispersed but, upon RAN translation, aggregate with the RAN translation products. These RNA-RAN protein agglomerates sequester various RNA-binding proteins and are associated with the disruption of nucleocytoplasmic transport and cell death. In contrast, RNA accumulation at nuclear foci alone does not produce discernable defects in nucleocytoplasmic transport or cell viability. Inhibition of RAN translation prevents cytoplasmic RNA aggregation and alleviates cell toxicity. Our findings demonstrate that RAN translation-induced RNA-protein aggregation correlates with the key pathological hallmarks observed in disease and suggest that cytoplasmic RNA aggregation may be an underappreciated phenomenon in CAG trinucleotide repeat expansion disorders.

Objective: There is increasing interest in simultaneous endovascular delivery of more than one drug from a drug-loaded stent into a diseased artery. There may be an opportunity to obtain a therapeutically desirable uptake profile of the two drugs over time by appropriate design of the initial drug distribution in the stent. Due to the non-linear, coupled nature of diffusion and reversible specific/non-specific binding of both drugs as well as competition between the drugs for a fixed binding site density, a comprehensive numerical investigation of this problem is critically needed., Methods: This paper presents numerical computation of dual drug delivery in a stent-artery system, accounting for diffusion as well as specific and non-specific reversible binding. The governing differential equations are discretized in space, followed by integration over time using a stiff numerical solver. Three different cases of initial dual drug distribution are considered., Results: For the particular case of sirolimus and paclitaxel, results show that competition for a limited non-specific binding site density and the significant difference in the forward/backward reaction coefficients play a key role in determining the nature of drug uptake. The nature of initial distribution of the two drugs in the stent is also found to influence the binding process, which can potentially be used to engineer a desirable dual drug uptake profile., Conclusions: These results help improve the fundamental understanding of endovascular dual drug delivery. In addition, the numerical technique and results presented here may be helpful for designing and optimizing other drug delivery problems as well., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Competing Interests: Ethical ApprovalAll procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Ethics clearance was obtained, and informed consent was taken from patient. This is to declare that all authors have contributed to the study. No part of the manuscript has been sent for consideration elsewhere or published in any international or national journal. The authors clearly certify that there is no aspect of plagiarism. All the conflicts of interest have been clearly defined and the source of grant disclosed. Due ethical permission/consent has been obtained for carrying out the study. In case of any dispute, the authors will be held fully responsible for the statement disclosed in the cover letter. The authors are also aware of the copyright rules and also declare that they will not reproduce any published text without due permission from the journal.Conflict of InterestThe authors declare no competing interests.

During the COVID-19 pandemic, public health agencies implemented an array of technologies and digital tools to support case investigation and contact tracing. Beginning in May 2020, the Association of State and Territorial Health Officials compiled information on digital tools used by its membership, which comprises 59 chief health officials from each of the 50 states, 5 US territories, 3 freely associated states, and the District of Columbia. This information was presented online through a publicly available technology and digital tools inventory. We describe the national landscape of digital tools implemented by public health agencies to support functions of the COVID-19 response from May 2020 through May 2021. We also discuss how public health officials and their informatics leadership referenced the information about the digital tools implemented by their peers to guide and refine their own implementation plans. We used a consensus-based approach through monthly discussions with partners to group digital tools into 5 categories: surveillance systems, case investigation, proximity technology/exposure notification, contact tracing, and symptom tracking/monitoring. The most commonly used tools included the National Electronic Disease Surveillance System Base System (NBS), Sara Alert, REDCap, and Maven. Some tools such as NBS, Sara Alert, REDCap, Salesforce, and Microsoft Dynamics were repurposed or adapted for >1 category. Having access to the publicly available technology and digital tools inventory provided public health officials and their informatics leadership with information on what tools other public health agencies were using and aided in decision making as they considered repurposing existing tools or adopting new ones.

The superior hydrogen storage properties makes the KSiH 3 system a potential hydrogen storage material for practical applications. A theoretical capacity of 4.3 wt% bring this material to the front line of all the available hydrogen storage materials; however, the activation barrier of the reaction restricts the system to absorb and desorb hydrogen reversibly at elevated temperatures even if the thermodynamics suggest its room temperature operation. Several catalysts have already been tested to enhance its kinetic properties. In this work, the efforts were made to reduce the activation energy by using Zr-based catalysts to the KSi/KSiH 3 system. The value of activation energy was found to be lowest (i.e., 87 kJ mol -1) for the ZrH 2 -added KSiH 3 system. The mechanism of this improvement was investigated by using X-ray photoelectron spectroscopy (XPS).

Objective: Customization of the rate of drug delivered based on individual patient requirements is of paramount importance in the design of drug delivery devices. Advances in manufacturing may enable multilayer drug delivery devices with different initial drug distributions in each layer. However, a robust mathematical understanding of how to optimize such capabilities is critically needed. The objective of this work is to determine the initial drug distribution needed in a spherical drug delivery device such as a capsule in order to obtain a desired drug release profile., Methods: This optimization problem is posed as an inverse mass transfer problem, and optimization is carried out using the solution of the forward problem. Both non-erodible and erodible multilayer spheres are analyzed. Cases with polynomial forms of initial drug distribution are also analyzed. Optimization is also carried out for a case where an initial burst in drug release rate is desired, followed by a constant drug release rate., Results: More than 60% reduction in root-mean-square deviation of the actual drug release rate from the ideal constant drug release rate is reported. Typically, the optimized initial drug distribution in these cases prevents or minimizes large drug release rate at early times, leading to a much more uniform drug release overall., Conclusions: Results demonstrate potential for obtaining a desired drug delivery profile over time by carefully engineering the drug distribution in the drug delivery device. These results may help engineer devices that offer customized drug delivery by combining advanced manufacturing with mathematical optimization., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Metal-organic frameworks (MOFs) represent a class of nanoporous materials built up by metal ions and organic linkers with several interesting potential applications. The present study described the synthesis and characterization of Gd(III)-based MOF with the chemical composition [Gd(BTC)(H 2 O)]·DMF (BTC - trimesate, DMF = N,N'-dimethylformamide), known as MOF-76(Gd) for hydrogen adsorption/desorption capacity and humidity sensing applications. The structure and morphology of as-synthesized material were studied using powder X-ray diffraction, scanning and transmission electron microscopy. The crystal structure of MOF-76(Gd) consists of gadolinium (III) and benzene-1,3,5-tricarboxylate ions, one coordinated aqua ligand and one crystallization DMF molecule. The polymeric framework of MOF-76(Gd) contains 1D sinusoidally shaped channels with sizes of 6.7 × 6.7 Å propagating along c crystallographic axis. The thermogravimetric analysis, heating infrared spectroscopy and in-situ heating powder X-ray diffraction experiments of the prepared framework exhibited thermal stability up to 550 °C. Nitrogen adsorption/desorption measurement at -196 °C showed a BET surface area of 605 m 2  g -1 and pore volume of 0.24 cm 3  g -1 . The maximal hydrogen storage capacity of MOF-76(Gd) was 1.66 wt % and 1.34 wt % -196 °C and -186 °C and pressure up to 1 bar, respectively. Finally, the humidity sensing measurements (water adsorption experiments) were performed, and the results indicate that MOF-76(Gd) is a suitable material for moisture sensing application with a fast response (11 s) and recovery time (2 s) in the relative humidity range of 11-98%., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Competing Interests: There are no conflicts of interest.

The hunt for a cleaner energy carrier leads us to consider a source that produces no toxic byproducts. One of the targeted alternatives in this approach is hydrogen energy, which, unfortunately, suffers from a lack of efficient storage media. Solid-state hydrogen absorption systems, such as lithium amide (LiNH 2 ) systems, may store up to 6.5 weight percent hydrogen. However, the temperature of hydrogenation and dehydrogenation is too high for practical use. Various molar ratios of LiNH 2 with sodium hydride (NaH) and potassium hydride (KH) have been explored in this paper. The temperature of hydrogenation for LiNH 2 combined with KH and NaH was found to be substantially lower than the temperature of individual LiNH 2 . This lower temperature operation of both LiNH 2 -NaH and LiNH 2 -KH systems was investigated in depth, and the eutectic melting phenomenon was observed. Systematic thermal studies of this amide-hydride system in different compositions were carried out, which enabled the plotting of a pseudo-binary phase diagram. The occurrence of eutectic interaction increased atomic mobility, which resulted in the kinetic modification followed by an increase in the reactivity of two materials. For these eutectic compositions, i.e., 0.15LiNH 2 -0.85NaH and 0.25LiNH 2 -0.75KH, the lowest melting temperature was found to be 307 °C and 235 °C, respectively. Morphological studies were used to investigate and present the detailed mechanism linked with this phenomenon.

Controlled release of a drug contained in a spherical polymer capsule is of significant interest in many fields of medicine. There is growing interest in tailoring the erosion properties of the drug to help control and optimize the drug release process. Theoretical understanding of the nature of drug release from a bioerodible capsule is, therefore, important for designing effective drug delivery systems. While drug release from a fixed-radius capsule is relatively easier to model, the shrinking nature of a bioerodible capsule due to surface erosion presents several difficulties in theoretical modeling. This work presents a closed-form solution for the drug concentration distribution and drug delivery characteristics from a spherical capsule undergoing linear surface erosion. This problem is solved by a transformation that converts the moving boundary problem into a fixed boundary problem. For uniform initial drug distribution, the solution is shown to depend on a single non-dimensional parameter. The theoretical model is used to develop an understanding of the impact of varying the drug diffusion coefficient and rate of erosion on drug delivery characteristics. It is found that, in general, the nature of drug release in a bioerodible sphere is determined by a delicate balance between two simultaneously occurring processes - erosion and diffusion. This work improves the theoretical understanding of diffusion in drug delivery systems by accounting for the practical erosion phenomena, and may contribute towards the design and optimization of drug delivery systems., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Competing Interests: Competing interests: The BMJ has judged that there are no disqualifying financial ties to commercial companies. The authors declare the following other interests: none.

Robust regulatory signals in the cell often depend on interactions between short linear motifs (SLiMs) and globular proteins. Many of these interactions are poorly characterized because the binding proteins cannot be produced in the amounts needed for traditional methods. To address this problem, we developed a single-molecule off-rate (SMOR) assay based on microscopy of fluorescent ligand binding to immobilized protein partners. We used it to characterize substrate binding to the Anaphase-Promoting Complex/Cyclosome (APC/C), a ubiquitin ligase that triggers chromosome segregation. We find that SLiMs in APC/C substrates (the D box and KEN box) display distinct affinities and specificities for the substrate-binding subunits of the APC/C, and we show that multiple SLiMs in a substrate generate a high-affinity multivalent interaction. The remarkably adaptable substrate-binding mechanisms of the APC/C have the potential to govern the order of substrate destruction in mitosis., (© 2022. The Author(s).)

Primary hyperparathyroidism is not so uncommon a disease. In high-income countries, with the introduction of routine biochemical testing in 1980s, it is diagnosed early, and the majority are seen as asymptomatic disease. However, in India, a severe symptomatic form is still seen, and many times patients are undiagnosed, thus continuing to suffer debilitating disease. Here, we report such a patient who was being treated as having bony metastases from an unknown primary source, when in fact he had osteitis fibrosa cystica due to primary hyperparathyroidism and was cured after surgery.

Haemolytic anaemia is a commonly encountered condition in clinical haematology practise. Dissecting the aetiology of haemolytic anaemia is of paramount importance for appropriate management. We describe a 29-years-old lady of Indian origin, who presented with fatigue and recurrent jaundice for 2 years. Examination revealed pallor, mild icterus, and splenomegaly. Blood tests showed anaemia, reticulocytosis, indirecthyperbilirubinemia, and high serum lactate dehydrogenase, consistent with haemolytic anaemia. Peripheral smear showed severely microcytic hypochromic red cells and polychromasia. Heinz bodies and inclusion bodies were seen with supravital staining. Haemoglobin high pressure liquid chromatography showed low HbA2 and normal HbF. Work-up for iron deficiency was negative. Polymerase chain reaction of the genomic DNA failed to identify common deletions in the HBA genes. Sangers sequencing of HBA2 gene revealed a homozygous missense mutation NM&#95;000517.6: c.391G > C (p.Ala131Pro) leading to a highly unstable hemoglobin, Hb Sun Prairie. Mother was heterozygous for the same mutation, and father was unavailable for genetic testing. We highlight the role of sangers sequencing in unravelling the underlying aetiology of haemolytic anaemia. Pathophysiology and existing literature of Hb Sun Prairie has been discussed., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 King Faisal Specialist Hospital & Research Centre. Published by Elsevier Ltd. All rights reserved.)