Trailblazing Kr/Xe Separation: The Birth of the First Kr-Selective Material.

Efficient separation of Kr from Kr/Xe mixtures is pivotal in nuclear waste management and dark matter research. Thus far, scientists have encountered a formidable challenge: the absence of a material with the ability to selectively adsorb Kr over Xe at room temperature. This study presents a groundbreaking transformation of the renowned metal-organic framework (MOF) CuBTC, previously acknowledged for its Xe adsorption affinity, into an unparalleled Kr-selective adsorbent. This achievement stems from an innovative densification approach involving systematic compression of the MOF, where the crystal size, interparticle interaction, defects, and evacuation conditions are synergistically modulated. The resultant densified CuBTC phase exhibits exceptional mechanical resilience, radiation tolerance, and notably an unprecedented selectivity for Kr over Xe at room temperature. Simulation and experimental kinetic diffusion studies confirm reduced gas diffusion in the densified MOF, attributed to its small pore window and minimal interparticle voids. The lighter Kr element demonstrates facile surface passage and higher diffusivity within the material, while the heavier Xe encounters increased difficulty entering the material and lower diffusivity. This Kr-selective MOF not only represents a significant breakthrough in Kr separation but also demonstrates remarkable processability and scalability to kilogram levels. The findings presented herein underscore the transformative potential of engineered MOFs in addressing complex challenges, heralding a new era of Kr separation technologies.

MolOptimizer: A Molecular Optimization Toolkit for Fragment-Based Drug Design.

MolOptimizer is a user-friendly computational toolkit designed to streamline the hit-to-lead optimization process in drug discovery. MolOptimizer extracts features and trains machine learning models using a user-provided, labeled, and small-molecule dataset to accurately predict the binding values of new small molecules that share similar scaffolds with the target in focus. Hosted on the Azure web-based server, MolOptimizer emerges as a vital resource, accelerating the discovery and development of novel drug candidates with improved binding properties.

Obesity, Metabolic Syndrome, and Osteoarthritis-An Updated Review.

PURPOSE OF REVIEW: Metabolic syndrome (MetS), also called the 'deadly quartet' comprising obesity, diabetes, dyslipidemia, and hypertension, has been ascertained to have a causal role in the pathogenesis of osteoarthritis (OA). This review is aimed at discussing the current knowledge on the contribution of metabolic syndrome and its various components to OA pathogenesis and progression. RECENT FINDINGS: Lately, an increased association identified between the various components of metabolic syndrome (obesity, diabetes, dyslipidemia, and hypertension) with OA has led to the identification of the 'metabolic phenotype' of OA. These metabolic perturbations alongside low-grade systemic inflammation have been identified to inflict detrimental effects upon multiple tissues of the joint including cartilage, bone, and synovium leading to complete joint failure in OA. Recent epidemiological and clinical findings affirm that adipokines significantly contribute to inflammation, tissue degradation, and OA pathogenesis mediated through multiple signaling pathways. OA is no longer perceived as just a 'wear and tear' disease and the involvement of the metabolic components in OA pathogenesis adds up to the complexity of the disease. Given the global surge in obesity and its allied metabolic perturbations, this review aims to throw light on the current knowledge on the pathophysiology of MetS-associated OA and the need to address MetS in the context of metabolic OA management. Better regulation of the constituent factors of MetS could be profitable in preventing MetS-associated OA. The identification of key roles for several metabolic regulators in OA pathogenesis has also opened up newer avenues in the recognition and development of novel therapeutic agents.

Placental mesenchymal stem cells restore glucose and energy homeostasis in obesogenic adipocytes.

Obesity (Ob) depicts a state of energy imbalance(s) being characterized by the accumulation of excessive fat and which predisposes to several metabolic diseases. Mesenchymal stem cells (MSCs) represent a promising option for addressing obesity and its associated metabolic co-morbidities. The present study aims at assessing the beneficial effects of human placental MSCs (P-MSCs) in mitigating Ob-associated insulin resistance (IR) and mitochondrial dysfunction both in vivo and in vitro. Under obesogenic milieu, adipocytes showed a significant reduction in glucose uptake, and impaired insulin signaling with decreased expression of UCP1 and PGC1α, suggestive of dysregulated non-shivering thermogenesis vis-a-vis mitochondrial biogenesis respectively. Furthermore, obesogenic adipocytes demonstrated impaired mitochondrial respiration and energy homeostasis evidenced by reduced oxygen consumption rate (OCR) and blunted ATP/NAD+/NADP+ production respectively. Interestingly, co-culturing adipocytes with P-MSCs activated PI3K-Akt signaling, improved glucose uptake, diminished ROS production, enhanced mitochondrial OCR, improved ATP/NAD+/NADP+ production, and promoted beiging of adipocytes evidenced by upregulated expression of PRDM16, UCP1, and PGC1α expression. In vivo, P-MSCs administration increased the peripheral blood glucose uptake and clearance, and improved insulin sensitivity and lipid profile with a coordinated increase in the ratio of ATP/ADP and NAD+ and NADP+ in the white adipose tissue (WAT), exemplified in WNIN/GR-Ob obese mutant rats. In line with in vitro findings, there was a significant reduction in adipocyte hypertrophy, increased mitochondrial staining, and thermogenesis. Our findings advocate for a therapeutic application of P-MSCs for improving glucose and energy homeostasis, i.e., probably restoring non-shivering thermogenesis towards obesity management.

Human placental mesenchymal stromal cell therapy restores the cytokine efflux and insulin signaling in the skeletal muscle of obesity-induced type 2 diabetes rat model.

Obesity poses a significant risk factor for the onset of metabolic syndrome with allied complications, wherein mesenchymal stem cell therapy is seen as a promising treatment for obesity-induced metabolic syndrome. In the present study, we aim to explore the beneficial effects of the human placental mesenchymal stromal cells (P-MSCs) on obesity-associated insulin resistance (IR) including inflammation. To understand this, we have analyzed the peripheral blood glucose, serum insulin levels by ELISA, and the glucose uptake capacity of skeletal muscle by a 2-NBDG assay using flow cytometry in WNIN/GR-Ob rats treated with and without P-MSCs. Also, we have studied insulin signaling and cytokine profile in the skeletal muscle by western blotting, dot blotting, and Multiplex-ELISA techniques. The skeletal muscle of WNIN/GR-Ob rats demonstrates dysregulation of cytokines, altered glucose uptake vis-a-vis insulin signaling. However, P-MSCs' treatment was effective in WNIN/GR-Ob rats as compared to its control, to restore HOMA-IR, re-establishes dysregulated cytokines and PI3K-Akt pathway in addition to enhanced Glut4 expression and glucose uptake studied in skeletal muscle. Overall, our data advocate the beneficial effects of P-MSCs to ameliorate inflammatory milieu, improve insulin sensitivity, and normalize glucose homeostasis underlining the Ob-T2D conditions, and we attribute for immunomodulatory, paracrine, autocrine, and multipotent functions of P-MSCs.

Beneficial effects of secretome derived from mesenchymal stem cells with stigmasterol to negate IL-1ß-induced inflammation in-vitro using rat chondrocytes-OA management.

Osteoarthritis (OA) is the most prevalent joint disease predominantly characterized by inflammation which drives cartilage destruction. Mesenchymal stem cells-condition medium (MSC-CM) or the secretome is enriched with bioactive factors and possesses anti-inflammatory and regenerative effects. The present study aimed at evaluating the effects of combining MSC-conditioned medium with stigmasterol compared with the individual treatments in alleviating interleukin-1 beta (IL-1ß)-induced inflammation in rat chondrocytes. Stigmasterol is a phytosterol exhibiting anti-inflammatory effects. IL-1ß (10 ng/ml) was used to induce inflammation and mimic OA in-vitro in primary rat articular chondrocytes. The IL-1ß-stimulated chondrocytes were treated with MSC-CM, stigmasterol, and a combination of MSC-CM and stigmasterol for 24 h. Cell viability was measured using MTT assay. Protein expression of inducible nitric oxide synthase (iNOS), interleukin-6 (IL-6), collagen II (COL2A1) and matrix metalloproteinase (MMP)-13 were evaluated by immunofluorescence. Gene expression levels of MMP-3, MMP-13 and A Disintegrin-like and Metalloproteinases with Thrombospondin Motifs (ADAMTS)-5 were measured using qRT-PCR. NF-κB signaling pathway was studied using western blotting. A significant reduction in the expression of iNOS, IL-6, MMP-3, MMP-13 and ADAMTS-5, and a significant increase in COL2A1 expression was observed in the rat chondrocytes across all the treatment groups. However, the combination treatment of MSC-CM and stigmasterol remarkably reversed the IL-1ß-induced pro-inflammatory/pro-catabolic responses to near normal levels comparable to the control group. The combination treatment (MSC-CM + stigmasterol) elicited a superior anti-inflammatory/anti-catabolic effect by inhibiting the IL-1ß-induced NF-κB activation evidenced by the negligible phosphorylation of p65 and IκBα subunits, thereby emphasizing the benefit of the combination therapy over the individual treatments.

The promise(s) of mesenchymal stem cell therapy in averting preclinical diabetes: lessons from in vivo and in vitro model systems.

Obesity (Ob) poses a significant risk factor for the onset of metabolic syndrome with associated complications, wherein the Mesenchymal Stem Cell (MSC) therapy shows pre-clinical success. Here, we explore the therapeutic applications of human Placental MSCs (P-MSCs) to address Ob-associated Insulin Resistance (IR) and its complications. In the present study, we show that intramuscular injection of P-MSCs homed more towards the visceral site, restored HOMA-IR and glucose homeostasis in the WNIN/GR-Ob (Ob-T2D) rats. P-MSC therapy was effective in re-establishing the dysregulated cytokines. We report that the P-MSCs activates PI3K-Akt signaling and regulates the Glut4-dependant glucose uptake and its utilization in WNIN/GR-Ob (Ob-T2D) rats compared to its control. Our data reinstates P-MSC treatment's potent application to alleviate IR and restores peripheral blood glucose clearance evidenced in stromal vascular fraction (SVF) derived from white adipose tissue (WAT) of the WNIN/GR-Ob rats. Gaining insights, we show the activation of the PI3K-Akt pathway by P-MSCs both in vivo and in vitro (palmitate primed 3T3-L1 cells) to restore the insulin sensitivity dysregulated adipocytes. Our findings suggest a potent application of P-MSCs in  pre-clinical/Ob-T2D management.

Characteristics of Serrated Adenomas in Non-Hispanic Whites and African Americans Undergoing Screening Colonoscopy.

Background and aim Adenomatous polyps are precursor lesions for colorectal cancer (CRC). Serrated adenomas/polyps are considered a risk factor for the development of proximal and interval CRC. African-Americans are at higher risk for right-sided CRC. Minimal data evaluating serrated adenoma characteristics by race/ethnicity on initial screening colonoscopy (SC) exist. The aim of this investigation was to compare the characteristics of serrated adenomas found in non-Hispanic whites (nHw) and African-Americans (AA) undergoing initial SC. Methods The University of Florida-Jacksonville endoscopy database was searched for all SC performed between January 2000 and December 2014. Inclusion criteria were nHw or AA race/ethnicity and histologically proven serrated adenoma found at SC. Data were collected for all included age at SC, sex, number, location, and size of serrated adenomas found. Results A total of 8693 individuals (nHw - 4199 and AA - 4494) underwent SC between January 2000 and December 2014. Serrated adenomas were found in 479 individuals (nHw, n=294; AA, n=185), and AA were significantly less likely than nHw to have serrated adenomas on SC (AA 4.1% vs nHw 7%; p< 0.0001). No difference was observed in mean age, location, or size between nHw and AA with serrated adenomas. Conclusions Serrated adenomas are more frequent in nHw compared to AA at initial SC. No difference was seen in size or location of serrated adenomas, as well as patient age, between AA and nHw. A study of genetic factors predisposing to serrated adenoma formation and the impact of socioeconomic disparities should be performed across ethnic groups to understand this difference.

A novel therapeutic combination of mesenchymal stem cells and stigmasterol to attenuate osteoarthritis in rodent model system-a proof of concept study.

Mesenchymal stem cells (MSCs) have gained wide therapeutic acceptance in regenerative medicine due to their potential in repair process in restoring the damaged tissues and controlling inflammation. In the present study, we report for the first time the beneficial effects of combining placental-derived MSCs (hPMSCs) with stigmasterol-a plant-derived sterol to accelerate cartilage repair and regeneration in a monosodium-iodoacetate (MIA) induced osteoarthritis (OA) rat model. Control animals (Group I) received no treatment. Experimental animals (Group II) received a single intra-articular injection of MIA (2 mg) in the right knee joints. The Group II animals developed OA-like lesions within a week of MIA injection. They were subdivided further as: (II-A): OA, (II-B): OA+hPMSCs (2×106 cells, single-dose/intra-articular injection), (II-C): OA+stigmasterol (20 µg/mL, single-dose/intra-articular injection) and (II-D): OA+hPMSCs+stigmasterol. The animals were monitored for four more weeks after which they were sacrificed, the right limbs dissected out and assessed for cartilage repair and regeneration using micro-computed tomography (micro-CT) and histology. Results showed that the combined administration of hPMSCs with stigmasterol (II-D) was the most effective in correcting the OA lesions, with concomitant repair and regeneration. However, hPMSCs (II-B) or stigmasterol (II-C) per se treated groups showed only marginal beneficial effects and were not significant. Thus the present study provides valuable insights in situ using a combination of hPMSCs and stigmasterol towards cartilage repair and regeneration. We advocate the participation of populating cells or residual chondrocytes in addition to its anti-inflammatory functions.

Monochorionic Diamniotic Vasa Previa Pregnancy: A Medical Student Perspective.

Monochorionic diamniotic twins and vasa previa are uncommon. We present a case that was followed from ultrasound diagnosis to delivery.

Metabolic Syndrome Predisposes to Osteoarthritis: Lessons from Model System.

OBJECTIVE: The present study aims to assess for temporal changes in tibial subchondral bone and cartilage in WNIN/Gr-Ob rats (portraying obesity, insulin resistance, dyslipidemia, impaired glucose tolerance, hypertension) in comparison with Wistar controls (WNIN) using anthropometry, micro-computed tomography (micro-CT), scanning electron microscopy (SEM), histopathology, enzyme-linked immunosorbent assay (ELISA), and immunofluorescence. DESIGN: Body weight, abdominal circumference, body mass index (BMI), lean/fat mass, serum tumor necrosis factor (TNF)-α levels were measured (ELISA), followed by ultrastructural analysis of tibial subchondral bone (micro-CT) and cartilage architecture (histopathology and SEM) in WNIN/Gr-Ob and WNIN rats with age (3, 6 and 9 months). Additionally, primary cultures of articular chondrocytes isolated from 6-month-old WNIN/Gr-Ob and WNIN rats were assessed for matrix metalloproteinase (MMP)-13 and Collagen type II (COL2A1) by immunofluorescence. RESULTS: WNIN/Gr-Ob rats exhibited frank obesity with increased BMI, lean and fat mass vis-à-vis significantly higher levels of serum TNF-α (6>9>3 months) as compared with the controls. With an increase in BMI, WNIN/Gr-Ob rats presented with tibial cartilage fibrillation, erosion, osteophyte formation (6 months) and subchondral bone cyst (9 months) confirmed by histology and SEM. An increase in subchondral trabecular bone volume (sclerosis with decreased plate porosity) was observed in all ages in WNIN/Gr-Ob rats compared to their Control. Gaining insights, primary cultures of articular chondrocytes complemented with altered cellular expressions of COL2A1 and MMP-13 from WNIN/Gr-Ob rats, indicating osteoarthritis (OA) progression. CONCLUSION: Multiple metabolic perturbations featured in WNIN/Gr-Ob rats were effective to induce spontaneous OA-like degenerative changes affecting knee joints akin to human OA.

Wet-Side Breath-Enhanced Jet Nebulization: Controlling Drug Delivery During Mechanical Ventilation.

BACKGROUND: The present study tested a novel nebulizer and circuit that use breath enhancement and breath actuation to minimize ventilator influences. The unique circuit design incorporates "wet-side" jet nebulization (the nebulizer connected to the humidifier outlet port) to prevent unpredictable aerosol losses with active humidification. The system was studied using several ventilator brands over a wide range of settings, with and without humidification. METHODS: During treatment, a 2-position valve directed all ventilator flow to the nebulizer, providing breath enhancement during inspiration. Aerosol was generated by air 50 psi 3.5 L/m triggered during inspiration by a pressure-sensitive circuit. Particles were captured on an inhaled mass filter. Testing was performed by using active humidification or bypassable valved heat and moisture exchanger (HME) over a range of breathing patterns, ventilator modes, and bias flows (0.5-5.0 L/m). The nebulizer was charged with 6 mL of radiolabeled saline solution. Mass balance was performed by using a gamma camera. Tidal volume was monitored by ventilator volume (exhaled VT) and test lung volume. The Mann-Whitney test was used. RESULTS: A total of 6 mL was nebulized within 1 h. Inhaled mass (% neb charge): mean ± SD (all data) 31.1% ± 6.45; no. = 83. Small significant differences were seen with humidification for all modes (humidified 36.1% ± 5.60, no. = 26; bypassable valved HME 28.8% ± 5.51, no. = 57 [P < .001]), continuous mandatory ventilation modes [P < .001], and pressure support airway pressure release ventilation modes [P < .001]. Mass median aerodynamic diameter ranged from 1.04 to 1.34 µm. The VT was unaffected (exhaled VT -5.0 ± 12.9 mL; P = .75) and test lung (test lung volume 25 ± 14.5 mL; P = .13). Bias flow and PEEP had no effect. CONCLUSIONS: Breath enhancement with breath actuation provided a predictable dose at any ventilator setting or type of humidification. Preservation of drug delivery during active humidification is a new finding, compared with previous studies. The use of wall gases and stand alone breath actuation standardizes conditions that drive the nebulizer independent of ventilator design. Wet-side nebulizer placement at the humidifier outlet allows delivery without introducing aerosol into the humidification chamber.

Maximizing Deep Lung Deposition in Healthy and Fibrotic Subjects During Jet Nebulization.

Background: In volunteers with idiopathic pulmonary fibrosis (IPF), inhaled Interferon-γ (IFN-γ) is safe and may improve pulmonary function. However, coughing, associated with upper airway deposition, is often reported. To address this problem, a small-particle, breath-enhanced jet nebulizer (i-NEB Mini; InspiRx, Inc., Somerset, NJ) was developed. Using gamma scintigraphy, this device was tested in healthy individuals and subjects with IPF to determine efficiency and regional deposition in lung and airways. Methods: Four healthy individuals and nine subjects with IPF were enrolled. The nebulizer was filled with 2 mL of saline with 99m Tc bound to diethylenetriaminepentaacetic acid (DTPA) powered continuously with 3.4 L/min of compressed air. Mass median aerodynamic diameter (MMAD) was measured by cascade impactor. To maximize deposition in alveoli, inspiratory flow was limited by an inspiratory resistance incorporated into the nebulizer, resulting in a deep inspiration ∼6 seconds. The treatment was run to completion (10 minutes), and each subject underwent deposition imaging. Mass balance and regions of interest determined upper airway (measured by calibrated stomach activity) and regional lung deposition as a percent of pretreatment nebulizer charge. Results: Subjects tolerated the device with no complaints. MMAD (mean [geometric standard deviation]) = 1.04 [1.92] µm. Lung deposition (mean ± standard error, % nebulizer charge) in healthy subjects was 26.2% ± 1.83 and in IPF individuals 23.4% ± 1.60 (p = 0.414). Upper airway deposition was 1.4% ± 0.83 and 2.3% ± 0.48, respectively (p = 0.351), and 20.1% was lost during expiration. Central/Peripheral ratios were consistent in both groups, showing high peripheral deposition (1.32 ± 0.050, vs. 1.28 ± 0.046, p = 0.912). Conclusion: The i-NEB Mini jet nebulizer with breath enhancement produced small particles, resulting in minimal upper airway deposition. Using slow and deep breathing, more than half of the emitted dose deposited in the peripheral lung in normal subjects and individuals with IPF. These data indicate that, for future clinical trials, controlled lung doses of small particles, designed to avoid coughing, are possible even in subjects with advanced disease.

Emerging Therapeutic Targets for Metabolic Syndrome: Lessons from Animal Models.

BACKGROUND: Metabolic syndrome is a cluster of medical conditions that synergistically increase the risk of heart diseases and diabetes. The current treatment strategy for metabolic syndrome focuses on treating its individual components. A highly effective agent for metabolic syndrome has yet to be developed. To develop a target for metabolic syndrome, the mechanism encompassing different organs - nervous system, pancreas, skeletal muscle, liver and adipose tissue - needs to be understood. Many animal models have been developed to understand the pathophysiology of metabolic syndrome. Promising molecular targets have emerged while characterizing these animals. Modulating these targets is expected to treat some components of metabolic syndrome. OBJECTIVE: To discuss the emerging molecular targets in an animal model of metabolic syndrome. METHODS: A literature search was performed for the retrieval of relevant articles. CONCLUSION: Multiple genes/pathways that play important role in the development of Metabolic Syndrome are discussed.

Antibiotics May Trigger Mitochondrial Dysfunction Inducing Psychiatric Disorders.

Clinical usage of several classes of antibiotics is associated with moderate to severe side effects due to the promotion of mitochondrial dysfunction. We contend that this may be due to perturbation of unique evolutionary relationships that link selective biochemical and molecular aspects of mitochondrial biology to conserved enzymatic processes derived from bacterial progenitors. Operationally, stereo-selective conformational matching between mitochondrial respiratory complexes, cytosolic and nuclear signaling complexes appears to support the conservation of a critically important set of chemical messengers required for existential regulation of homeostatic cellular processes. Accordingly, perturbation of normative mitochondrial function by select classes of antibiotics is certainly reflective of the high degree of evolutionary pressure designed to maintain ongoing bidirectional signaling processes between cellular compartments. These issues are of critical importance in evaluating potentially severe side effects of antibiotics on complex behavioral functions mediated by CNS neuronal groups. The CNS is extremely dependent on delivery of molecular oxygen for maintaining a required level of metabolic activity, as reflected by the high concentration of neuronal mitochondria. Thus, it is not surprising to find several distinct behavioral abnormalities conforming to established psychiatric criteria that are associated with antibiotic usage in humans. The manifestation of acute and/or chronic psychiatric conditions following antibiotic usage may provide unique insights into key etiological factors of major psychiatric syndromes that involve rundown of cellular bioenergetics via mitochondrial dysfunction. Thus, a potential window of opportunity exists for development of novel therapeutic agents targeting diminished mitochondrial function as a factor in severe behavioral disorders.

Morphine stimulates nitric oxide release in human mitochondria.

The expression of morphine by plants, invertebrate, and vertebrate cells and organ systems, strongly indicates a high level of evolutionary conservation of morphine and related morphinan alkaloids as required for life. The prototype catecholamine, dopamine, serves as an essential chemical intermediate in morphine biosynthesis, both in plants and animals. We surmise that, before the emergence of specialized plant and animal cells/organ systems, primordial multi-potential cell types required selective mechanisms to limit their responsiveness to environmental cues. Accordingly, cellular systems that emerged with the potential for recruitment of the free radical gas nitric oxide (NO) as a multi-faceted autocrine/paracrine signaling molecule, were provided with extremely positive evolutionary advantages. Endogenous morphinergic signaling, in concert with NO-coupled signaling systems, has evolved as an autocrine/paracrine regulator of metabolic homeostasis, energy metabolism, mitochondrial respiration and energy production. Basic physiological processes involving morphinergic/NO-coupled regulation of mitochondrial function, with special emphasis on the cardiovascular system, are critical to all organismic survival. Key to this concept may be the phenomenon of mitochondrial enslavement in eukaryotic evolution via endogenous morphine.

Comparing bioinformatic gene expression profiling methods: microarray and RNA-Seq.

Understanding the control of gene expression is critical for our understanding of the relationship between genotype and phenotype. The need for reliable assessment of transcript abundance in biological samples has driven scientists to develop novel technologies such as DNA microarray and RNA-Seq to meet this demand. This review focuses on comparing the two most useful methods for whole transcriptome gene expression profiling. Microarrays are reliable and more cost effective than RNA-Seq for gene expression profiling in model organisms. RNA-Seq will eventually be used more routinely than microarray, but right now the techniques can be complementary to each other. Microarrays will not become obsolete but might be relegated to only a few uses. RNA-Seq clearly has a bright future in bioinformatic data collection.