Deficiency of a sulfotransferase for sialic acid-modified glycans mitigates Alzheimer's pathology.

We previously showed that microglial keratan sulfate (KS) was induced in amyotrophic lateral sclerosis. However, the functional roles of the glycan and its synthetic enzyme in neurodegenerative diseases, such as Alzheimer's disease (AD), a progressive disorder, are unclear. In our study, KS modified with sialic acids having a molecular mass of 125-220 kDa and the carbohydrate sulfotransferase GlcNAc6ST1 were up-regulated in the brains of two transgenic mouse models (J20 and Tg2576) and the brains of patients with AD. GlcNAc6ST1-deficient J20 (J20/GlcNAc6ST1-/-) mice demonstrated a complete absence of the microglial sialylated KS. J20/GlcNAc6ST1-/- primary microglia showed an increased level of amyloid-ß phagocytosis and were hyperresponsive to interleukin 4, a potent antiinflammatory cytokine. Moreover, J20/GlcNAc6ST1-/- mice manifested reduced cerebral amyloid-ß deposition. GlcNAc6ST1-synthesizing sialylated KS thus modulates AD pathology. Inhibition of KS synthesis by targeting GlcNAc6ST1 may therefore be beneficial for controlling AD pathogenesis.

Microglial keratan sulfate epitope elicits in central nervous tissues of transgenic model mice and patients with amyotrophic lateral sclerosis.

The functional role of 5D4 antibody-reactive keratan sulfate (KS) in the pathogenesis of neurodegenerative diseases is unknown. We therefore studied the expression of 5D4-reactive KS in amyotrophic lateral sclerosis (ALS), a motor neuron-degenerative disease, with the use of SOD1(G93A) ALS model mice and patients with ALS. Histochemical and immunoelectron microscopic characterizations showed that the 5D4-reactive KS is expressed in Mac2/galectin-3-positive activated or proliferating microglia of SOD1(G93A) ALS model mice at disease end stage and that the KS is an O-linked glycan modified with sialic acid and fucose, which was thus far shown to exist in cartilage. Intriguingly, microglial KS was detected in the spinal cord and brainstem but not in the cerebral cortex of SOD1(G93A) mice. We found that KSGal6ST, a galactose-6-sulfotransferase, is required for biosynthesis of the microglial 5D4-reactive KS by generating SOD1(G93A)/KSGal6ST(-/-) mice. The requirement of GlcNAc6ST1 for this synthesis was corroborated by analyzing SOD1(G93A)/GlcNAc6ST1(-/-) mice. These results indicate that both galactose-6- and N acteylglucosamine-6-sulfated KS elicited in the spinal cord and brainstem are associated with the degeneration of spinal and bulbar lower motor neurons in ALS pathology and may play a role in disease progression via microglial activation and proliferation.

Emerging biologics for the treatment of pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a rare pulmonary vascular disorder, wherein mean systemic arterial pressure (mPAP) becomes abnormally high because of aberrant changes in various proliferative and inflammatory signalling pathways of pulmonary arterial cells. Currently used anti-PAH drugs chiefly target the vasodilatory and vasoconstrictive pathways. However, an imbalance between bone morphogenetic protein receptor type II (BMPRII) and transforming growth factor beta (TGF-ß) pathways is also implicated in PAH predisposition and pathogenesis. Compared to currently used PAH drugs, various biologics have shown promise as PAH therapeutics that elicit their therapeutic actions akin to endogenous proteins. Biologics that have thus far been explored as PAH therapeutics include monoclonal antibodies, recombinant proteins, engineered cells, and nucleic acids. Because of their similarity with naturally occurring proteins and high binding affinity, biologics are more potent and effective and produce fewer side effects when compared with small molecule drugs. However, biologics also suffer from the limitations of producing immunogenic adverse effects. This review describes various emerging and promising biologics targeting the proliferative/apoptotic and vasodilatory pathways involved in PAH pathogenesis. Here, we have discussed sotatercept, a TGF-ß ligand trap, which is reported to reverse vascular remodelling and reduce PVR with an improved 6-minute walk distance (6-MWDT). We also elaborated on other biologics including BMP9 ligand and anti-gremlin1 antibody, anti-OPG antibody, and getagozumab monoclonal antibody and cell-based therapies. Overall, recent literature suggests that biologics hold excellent promise as a safe and effective alternative to currently used PAH therapeutics.

Bio-Inspired Nanomaterials for Micro/Nanodevices: A New Era in Biomedical Applications.

Exploring bio-inspired nanomaterials (BINMs) and incorporating them into micro/nanodevices represent a significant development in biomedical applications. Nanomaterials, engineered to imitate biological structures and processes, exhibit distinctive attributes such as exceptional biocompatibility, multifunctionality, and unparalleled versatility. The utilization of BINMs demonstrates significant potential in diverse domains of biomedical micro/nanodevices, encompassing biosensors, targeted drug delivery systems, and advanced tissue engineering constructs. This article thoroughly examines the development and distinctive attributes of various BINMs, including those originating from proteins, DNA, and biomimetic polymers. Significant attention is directed toward incorporating these entities into micro/nanodevices and the subsequent biomedical ramifications that arise. This review explores biomimicry's structure-function correlations. Synthesis mosaics include bioprocesses, biomolecules, and natural structures. These nanomaterials' interfaces use biomimetic functionalization and geometric adaptations, transforming drug delivery, nanobiosensing, bio-inspired organ-on-chip systems, cancer-on-chip models, wound healing dressing mats, and antimicrobial surfaces. It provides an in-depth analysis of the existing challenges and proposes prospective strategies to improve the efficiency, performance, and reliability of these devices. Furthermore, this study offers a forward-thinking viewpoint highlighting potential avenues for future exploration and advancement. The objective is to effectively utilize and maximize the application of BINMs in the progression of biomedical micro/nanodevices, thereby propelling this rapidly developing field toward its promising future.

Rapid diagnosis of COVID-19 via nano-biosensor-implemented biomedical utilization: a systematic review.

The novel human coronavirus pandemic is one of the most significant occurrences in human civilization. The rapid proliferation and mutation of Severe Acute Respiratory Syndrome-Coronavirus 2 (SARS-CoV-2) have created an exceedingly challenging situation throughout the world's healthcare systems ranging from underdeveloped countries to super-developed countries. The disease is generally recognized as coronavirus disease 2019 (COVID-19), and it is caused by a new human CoV, which has put mankind in jeopardy. COVID-19 is death-dealing and affects people of all ages, including the elderly and middle-aged people, children, infants, persons with co-morbidities, and immunocompromised patients. Moreover, multiple SARS-CoV-2 variants have evolved as a result of genetic alteration. Some variants cause severe symptoms in patients, while others cause an unusually high infection rate, and yet others cause extremely severe symptoms as well as a high infection rate. Contrasting with a previous epidemic, COVID-19 is more contagious since the spike protein of SARS-CoV-2 demonstrates profuse affection to angiotensin-converting enzyme II (ACE2) that is copiously expressed on the surface of human lung cells. Since the estimation and tracking of viral loads are essential for determining the infection stage and recovery duration, a quick, accurate, easy, cheap, and versatile diagnostic tool is critical for managing COVID-19, as well as for outbreak control. Currently, Reverse Transcription Polymerase Chain Reaction (RT-PCR) testing is the most often utilized approach for COVID-19 diagnosis, while Computed Tomography (CT) scans of the chest are used to assess the disease's stages. However, the RT-PCR method is non-portable, tedious, and laborious, and the latter is not capable of detecting the preliminary stage of infection. In these circumstances, nano-biosensors can play an important role to deliver point-of-care diagnosis for a variety of disorders including a wide variety of viral infections rapidly, economically, precisely, and accurately. New technologies are being developed to overcome the drawbacks of the current methods. Nano-biosensors comprise bioreceptors with electrochemical, optical, or FET-based transduction for the specific detection of biomarkers. Different types of organic-inorganic nanomaterials have been incorporated for designing, fabricating, and improving the performance and analytical ability of sensors by increasing sensitivity, adsorption, and biocompatibility. The particular focus of this review is to carry out a systematic study of the status and perspectives of synthetic routes for nano-biosensors, including their background, composition, fabrication processes, and prospective applications in the diagnosis of COVID-19.

Analysis of the suspected cancer-causing potassium bromate additive in bread samples available on the market in and around Dhaka City in Bangladesh.

Bread is one of the most popular foods consumed worldwide. It is a very popular foodstuff consumed in almost every house in Bangladesh as breakfast. Bread is prepared predominantly from flour to meet the daily carbohydrate demand and enhances its overall nutrition value using various ingredients. Potassium bromate (KBrO3) is an alluring additive to improve bread quality by bread makers. But due to the well-known toxic and carcinogenic effect, certain levels of KBrO3 residue are not suitable for bread, and it is therefore forbidden in many countries. The key objective of this study is to evaluate the safety status of bread in Dhaka City and its proximity to Bangladesh. Twenty-one randomly collected bread samples were tested in this study from different bakeries or shops in and around Dhaka City. The levels of KBrO3 were analyzed spectrophotometrically, and the maximum concentration found in the bread sample was 9.29 µg/g. A total of 67% of collected bread samples showed elevated levels of KBrO3 relative to the allowable amount prescribed by various Food and Drug Administration worldwide. KBrO3 is toxic to consumers and could endanger their health over continuous regular consumption and thus need to be monitored strictly.

Role of Ionic Moieties in Hydrogel Networks to Remove Heavy Metal Ions from Water.

A variety of methods for removing heavy metal ions from wastewater have been developed but because of their low efficiency, further production of toxic sludge or other waste materials, high expense, and lengthy procedures, limited progress has been achieved to date. Polymeric hydrogel has been attracting particular attention for the effective removal of heavy metal ions from wastewater. Here, ionogenic polymeric hydrogels were prepared by free-radical copolymerization of a neutral acrylamide (AAm) monomer with an ionic comonomer in the presence of a suitable initiator and a cross-linker. Different types of ionic comonomers such as strongly acidic: 2-acrylamido-2-methylpropane sulfonic acid, weakly acidic: acrylic acid (AAc), and zwitterionic: 2-methacryloyloxy ethyl dimethyl-3-sulfopropyl ammonium hydroxide with varying amounts were incorporated into the poly(AAm) networks to fabricate the hydrogels. The heavy metal ions (Fe3+, Cr3+, and Hg2+) removal capacity of the fabricated hydrogels from an aqueous solution via electrostatic interactions, coordination bond formation, and a diffusion process was compared and contrasted. The poly(AAm) hydrogel containing weakly acidic AAc groups shows excellent removal capacity of heavy metal ions. The release and recovery of heavy metal ions from the hydrogel samples are also impressive. The compressive strength of hydrogels was found to be significantly high after incorporating heavy metal ions that will increase their potential applications in different sectors.

GlcNAc6ST3 is a keratan sulfate sulfotransferase for the protein-tyrosine phosphatase PTPRZ in the adult brain.

Keratan sulfate (KS) is a carbohydrate side chain covalently attached to extracellular proteoglycans. KS is composed of disaccharide units of 6-sulfated N-acetylglucosamine (GlcNAc) and galactose. We have previously shown that GlcNAc-6-O-sulfotransferase (GlcNAc6ST) 1 encoded by Chst2 is an enzyme necessary for the synthesis of GlcNAc-6-sulfated KS chains that are required for neuronal plasticity in the visual cortex of the mouse brain during the critical period, but not in adulthood. Here, we show that GlcNAc-6-sulfated KS recognized by the R-10G anti-KS antibody, of which the minimum epitope structure is Galß1-4GlcNAc(6S)ß1-3Galß1-4GlcNAc(6S), distributes diffusely in neuropils and presents densely in close proximity to the perineuronal region of the perineuronal net (PNN)-positive neurons in the adult visual cortex. Surprisingly, GlcNAc6ST3, which was discovered as an intestinal GlcNAc6ST encoded by Chst5, is a major brain KS sulfotransferase expressed in oligodendrocytes in adulthood. Moreover, we identified an isoform of the protein-tyrosine phosphatase PTPRZ as a R-10G-reactive KS proteoglycan. These results indicate that GlcNAc6ST3 may play a role in synthesis of a component of PNN in the adult brain, and that the KS-modified isoform of PTPRZ encoded by Ptprz1 could be an extracellular molecule associated with PNNs.

KSGal6ST is essential for the 6-sulfation of galactose within keratan sulfate in early postnatal brain.

Keratan sulfate (KS) comprises repeating disaccharides of galactose (Gal) and N-acetylglucosamine (GlcNAc). Residues of Gal and GlcNAc in KS are potentially modified with sulfate at their C-6 positions. The 5D4 monoclonal antibody recognizes KS structures containing Gal and GlcNAc, both 6-sulfated, and has been used most extensively to evaluate KS expression in mammalian brains. We previously showed that GlcNAc6ST1 is an enzyme responsible for the synthesis of the 5D4 epitope in developing brain and in the adult brain, where it is induced after injury. It has been unclear which sulfotransferase is responsible for Gal-6-sulfation within the 5D4 KS epitope in developing brains. We produced mice deficient in KSGal6ST, a Gal-6-sulfotransferase. Western blotting and immunoprecipitation revealed that all 5D4-immunoreactivity to proteins, including phosphacan, were abolished in KSGal6ST-deficient postnatal brains. Likewise, the 5D4 epitope, expressed primarily in the cortical marginal zone and subplate and dorsal thalamus, was eliminated in KSGal6ST-deficient mice. Disaccharide analysis showed the loss of Gal-6-sulfate in KS of the KSGal6ST-deficient brains. Transfection studies revealed that GlcNAc6ST1 and KSGal6ST cooperated in the expression of the 5D4 KS epitope in HeLa cells. These results indicate that KSGal6ST is essential for C-6 sulfation of Gal within KS in early postnatal brains.