A Thiazole Coumarin (TC) turn-on fluorescence probe for AT-base pair detection and multipurpose applications in different biological systems

Sequence-specific recognition of DNA by small turn-on fluorescence probes is a promising tool for bioimaging, bioanalytical and biomedical applications. Here, the authors report a novel cell-permeable and red fluorescent hemicyanine-based Thiazole Coumarin (TC) probe for DNA recognition, nuclear staining and cell cycle analysis. TC exhibited strong fluorescence enhancement in the presence of DNA containing AT-base pairs, but did not fluoresce with GC sequences, single-stranded DNA, RNA and proteins. The fluorescence staining of HeLa S3 and HEK 293 cells by TC followed by DNase and RNase digestion studies depicted the selective staining of DNA in the nucleus over the cytoplasmic region. Fluorescence-Activated Cell Sorting (FACS) analysis by flow cytometry demonstrated the potential application of TC in cell cycle analysis in HEK 293 cells. Metaphase chromosome and malaria parasite DNA imaging studies further confirmed the in vivo diagnostic and therapeutic applications of probe TC. Probe TC may find multiple applications in fluorescence spectroscopy, diagnostics, bioimaging and molecular and cell biology

Global, regional, and national burden of disorders affecting the nervous system, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

BackgroundDisorders affecting the nervous system are diverse and include neurodevelopmental disorders, late-life neurodegeneration, and newly emergent conditions, such as cognitive impairment following COVID-19. Previous publications from the Global Burden of Disease, Injuries, and Risk Factor Study estimated the burden of 15 neurological conditions in 2015 and 2016, but these analyses did not include neurodevelopmental disorders, as defined by the International Classification of Diseases (ICD)-11, or a subset of cases of congenital, neonatal, and infectious conditions that cause neurological damage. Here, we estimate nervous system health loss caused by 37 unique conditions and their associated risk factors globally, regionally, and nationally from 1990 to 2021.MethodsWe estimated mortality, prevalence, years lived with disability (YLDs), years of life lost (YLLs), and disability-adjusted life-years (DALYs), with corresponding 95% uncertainty intervals (UIs), by age and sex in 204 countries and territories, from 1990 to 2021. We included morbidity and deaths due to neurological conditions, for which health loss is directly due to damage to the CNS or peripheral nervous system. We also isolated neurological health loss from conditions for which nervous system morbidity is a consequence, but not the primary feature, including a subset of congenital conditions (ie, chromosomal anomalies and congenital birth defects), neonatal conditions (ie, jaundice, preterm birth, and sepsis), infectious diseases (ie, COVID-19, cystic echinococcosis, malaria, syphilis, and Zika virus disease), and diabetic neuropathy. By conducting a sequela-level analysis of the health outcomes for these conditions, only cases where nervous system damage occurred were included, and YLDs were recalculated to isolate the non-fatal burden directly attributable to nervous system health loss. A comorbidity correction was used to calculate total prevalence of all conditions that affect the nervous system combined.FindingsGlobally, the 37 conditions affecting the nervous system were collectively ranked as the leading group cause of DALYs in 2021 (443 million, 95% UI 378–521), affecting 3·40 billion (3·20–3·62) individuals (43·1%, 40·5–45·9 of the global population); global DALY counts attributed to these conditions increased by 18·2% (8·7–26·7) between 1990 and 2021. Age-standardised rates of deaths per 100 000 people attributed to these conditions decreased from 1990 to 2021 by 33·6% (27·6–38·8), and age-standardised rates of DALYs attributed to these conditions decreased by 27·0% (21·5–32·4). Age-standardised prevalence was almost stable, with a change of 1·5% (0·7–2·4). The ten conditions with the highest age-standardised DALYs in 2021 were stroke, neonatal encephalopathy, migraine, Alzheimer's disease and other dementias, diabetic neuropathy, meningitis, epilepsy, neurological complications due to preterm birth, autism spectrum disorder, and nervous system cancer.InterpretationAs the leading cause of overall disease burden in the world, with increasing global DALY counts, effective prevention, treatment, and rehabilitation strategies for disorders affecting the nervous system are needed

Visible-near-infrared and fluorescent copper sensors based on julolidine conjugates: selective detection and fluorescence imaging in living cells

We present novel Schiff base ligands julolidine–carbonohydrazone 1 and julolidine–thiocarbonohydrazone 2 for selective detection of Cu<SUP>2+</SUP> in aqueous medium. The planar julolidine-based ligands can sense Cu<SUP>2+</SUP> colorimetrically with characteristic absorbance in the near-infrared (NIR, 700–1000 nm) region. Employing molecular probes 1 and 2 for detection of Cu<SUP>2+</SUP> not only allowed detection by the naked eye, but also detection of varying micromolar concentrations of Cu<SUP>2+</SUP> due to the appearance of distinct coloration. Moreover, Cu<SUP>2+</SUP> selectively quenches the fluorescence of julolidine–thiocarbonohydrazone 2 among all other metal ions, which increases the sensitivity of the probe. Furthermore, quenched fluorescence of the ligand 2 in the presence of Cu<SUP>2+</SUP> was restored by adjusting the complexation ability of the ligand. Hence, by treatment with ethylenediaminetetraacetic acid (EDTA), thus enabling reversibility and dual-check signaling, julolidine–thiocarbonohydrazone (2) can be used as a fluorescent molecular probe for the sensitive detection of Cu<SUP>2+</SUP> in biological systems. The ligands 1 and 2 can be utilized to monitor Cu<SUP>2+</SUP> in aqueous solution over a wide pH range. We have investigated the structural, electronic, and optical properties of the ligands using ab initio density functional theory (DFT) combined with time-dependent density functional theory (TDDFT) calculations. The observed absorption band in the NIR region is attributed to the formation of a charge-transfer complex between Cu<SUP>2+</SUP> and the ligand. The fluorescence-quenching behavior can be accounted for primarily due to the excited-state ligand 2 to metal (Cu<SUP>2+</SUP>) charge-transfer (LMCT) processes. Thus, experimentally observed characteristic NIR and fluorescence optical responses of the ligands upon binding to Cu<SUP>2+</SUP> are well supported by the theoretical calculations. Subsequently, we have employed julolidine–thiocarbonohydrazone 2 for reversible fluorescence sensing of intracellular Cu<SUP>2+</SUP> in cultured HEK293T cells

A switch-on near-infrared fluorescence-ready probe for Cu(I): live cell imaging

<div><p>A reaction-based strategy exploiting metal ion mediated oxidative C–O bond cleavage affords selective ‘switch-on’ near-infrared (NIR) emitting cyanine probe for Cu⁺ in aqueous media and live cells. Near-infrared fluorescence-ready probe <b>TPACy</b> readily reacts with Cu⁺ to release the quinone embedded heptamethine cyanine (<b>Cy-quinone</b>) with extended π-electron conjugation responsible for the switch-on NIR fluorescence in aqueous buffer solution (50 mM HEPES, pH 7.2). This probe can be conveniently used for monitoring Cu⁺ without the interference from pH dependent effects of physiological media. Utility of the probe has been demonstrated by its application in the detection of unbound copper species (Cu⁺) in live cells.</p></div

J. Neurosci.

Although the brain functions of specific acetyltransferases such as the CREB-binding protein (CBP) and p300 have been well documented using mutant transgenic mice models, studies based on their direct pharmacological activation are still missing due to the lack of cell-permeable activators. Here we present a small-molecule (TTK21) activator of the histone acetyltransferases CBP/p300, which, when conjugated to glucose-based carbon nanosphere (CSP), passed the blood-brain barrier, induced no toxicity, and reached different parts of the brain. After intraperitoneal administration in mice, CSP-TTK21 significantly acetylated histones in the hippocampus and frontal cortex. Remarkably, CSP-TTK21 treatment promoted the formation of long and highly branched doublecortin-positive neurons in the subgranular zone of the dentate gyrus and reduced BrdU incorporation, suggesting that CBP/p300 activation favors maturation and differentiation of adult neuronal progenitors. In addition, mRNA levels of the neuroD1 differentiation marker and BDNF, a neurotrophin required for the terminal differentiation of newly generated neurons, were both increased in the hippocampus concomitantly with an enrichment of acetylated-histone on their proximal promoter. Finally, we found that CBP/p300 activation during a spatial training, while not improving retention of a recent memory, resulted in a significant extension of memory duration. This report is the first evidence for CBP/p300-mediated histone acetylation in the brain by an activator molecule, which has beneficial implications for the brain functions of adult neurogenesis and long-term memory. We propose that direct stimulation of acetyltransferase function could be useful in terms of therapeutic options for brain diseases

Chemical Biology Research in India

Chemical biology, as the terminology suggests, is the intertwining of chemistry and biology. However, the exact definition of chemical biology has been constantly debated among the researchers working at the interface of chemistry and biology. One of the major differences between the closely related fields of biochemistry and chemical biology is that the former is more relevant to the actual physiological scenario, whereas the latter has a synthetic feel to it. Thus, exploring biology with the aid of chemical tools can be considered to be the main philosophy of chemical biology. The science of chemical biology in the present form is only about 2 decades old, and hence the successes and failures in this area are more in the limelight than many other fields of science. All over the world, there are active initiatives to merge this new area of research into the scientific mainstream. Universities such as MIT, Harvard, RIKEN, and McGill have full-fledged departments dedicated to chemical biology. Perhaps the earliest research institute in the world dedicated to chemical biology was the CSIR-Indian Institute of Chemical Biology in Kolkata, India. The 75-year-old research institute was reoriented and renamed in 1982 to its present form to explore the chemistry of life—with chemical and biochemical tools. In India, this exciting area of research has spread beyond this institute, and in this In Focus article we shall highlight the status of chemical biology research in India with respect to its past, present, and future. Although work at the interface of chemistry and biology is widespread in India, we will largely focus on institutions that use chemical tools to explore biology