ABSTRACT
FEM1B is a substrate-recognition component of the CRL2 E3 ubiquitin-protein ligase. This multi-protein complex targets specific proteins for ubiquitination, which leads to their degradation. Here, we demonstrate the regulation of FEM1B expression by stop codon readthrough (SCR). In this process, translating ribosomes readthrough the stop codon of FEM1B to generate a C-terminally extended highly unstable isoform. Eighty-one nucleotides in the proximal 3'UTR of FEM1B constitute the necessary and sufficient cis-signal for SCR. Also, they encode the amino acid sequence responsible for the degradation of the SCR product. CRISPR-edited cells lacking this region, and therefore SCR of FEM1B, showed increased FEM1B expression. This in turn resulted in reduced expression of SLBP (target of FEM1B for degradation) and replication-dependent histones (target of SLBP for mRNA stability), causing cell cycle delay. Evolutionary analysis revealed that this phenomenon is specific to the genus Pan and Homo (Hominini). Overall, we show a relatively recently evolved SCR process that relieves the cell cycle from the negative regulation by FEM1B.
ABSTRACT
Spatial transcriptomics has transformed our ability to study tissue complexity. However, it remains challenging to accurately dissect tissue organization at single-cell resolution. Here we introduce scHolography, a machine learning-based method designed to reconstruct single-cell spatial neighborhoods and facilitate 3D tissue visualization using spatial and single-cell RNA sequencing data. scHolography employs a high-dimensional transcriptome-to-space projection that infers spatial relationships among cells, defining spatial neighborhoods and enhancing analyses of cell-cell communication. When applied to both human and mouse datasets, scHolography enables quantitative assessments of spatial cell neighborhoods, cell-cell interactions, and tumor-immune microenvironment. Together, scHolography offers a robust computational framework for elucidating 3D tissue organization and analyzing spatial dynamics at the cellular level.
Subject(s)
Machine Learning , Single-Cell Analysis , Single-Cell Analysis/methods , Animals , Humans , Mice , Computational Biology/methods , Cell Communication , Transcriptome , Tumor MicroenvironmentABSTRACT
Key Clinical Message: Prompt identification and management of anti-N-methyl-D-aspartate receptor encephalitis in young patients with acute psychiatric symptoms, seizures, and neurological deficits are crucial. Timely immunomodulatory therapy is essential for positive outcomes and minimizing long-term complications. High suspicion for this rare disorder is necessary for timely diagnosis and optimal care. Abstract: Anti-N-methyl-D-aspartate (NMDA) receptor encephalitis is characterized by the presence of antibodies against the NMDA receptor, a crucial component of synaptic signaling. This autoimmune disorder often manifests with psychiatric symptoms, seizures, and neurological deficits. Early diagnosis is essential, as delayed treatment can result in severe complications. In this case, the patient received corticosteroids and intravenous immunoglobulin (IVIG), leading to a successful recovery with no lingering neurological abnormalities. The prompt initiation of treatment highlights the importance of recognizing this condition early. Anti-NMDA receptor encephalitis is a rare autoimmune disorder that presents with a range of neurological symptoms. In this case report, we highlight the significance of early recognition and treatment by discussing the emergency room visit of a 23-year-old woman who presented with acute-onset agitation, disorientation, and seizures. A 23-year-old woman, presented to the emergency room with acute-onset agitation, disorientation, and seizures. Magnetic resonance imaging (MRI) scans revealed temporal lobe signal alterations and electroencephalogram (EEG) showed widespread activity slowing. Importantly, anti-NMDA receptor antibodies were detected in both serum and cerebrospinal fluid, confirming the diagnosis of anti-NMDA receptor encephalitis. This case report underscores the significance of understanding the presentation, diagnosis, and treatment of anti-NMDA receptor encephalitis. Timely recognition and intervention are crucial for achieving favorable outcomes in patients with this rare but clinically important autoimmune disorder. Increased awareness among healthcare professionals is essential to ensure early diagnosis and prompt initiation of appropriate treatment strategies.
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Heavy metal (HM) poisoning of agricultural soils poses a serious risk to plant life, human health, and global food supply. When HM levels in agricultural soils get to dangerous levels, it harms crop health and yield. Chromium (Cr), arsenic (As), nickel (Ni), cadmium (Cd), lead (Pb), mercury (Hg), zinc (Zn), and copper (Cu) are the main heavy metals. The environment contains these metals in varying degrees, such as in soil, food, water, and even the air. These substances damage plants and alter soil characteristics, which lowers crop yield. Crop types, growing circumstances, elemental toxicity, developmental stage, soil physical and chemical properties, and the presence and bioavailability of heavy metals (HMs) in the soil solution are some of the factors affecting the amount of HM toxicity in crops. By interfering with the normal structure and function of cellular components, HMs can impede various metabolic and developmental processes. Humans are exposed to numerous serious diseases by consuming these affected plant products. Exposure to certain metals can harm the kidneys, brain, intestines, lungs, liver, and other organs of the human body. This review assesses (1) contamination of heavy metals in soils through different sources, like anthropogenic and natural; (2) the effect on microorganisms and the chemical and physical properties of soil; (3) the effect on plants as well as crop production; and (4) entering the food chain and associated hazards to human health. Lastly, we identified certain research gaps and suggested further study. If people want to feel safe in their surroundings, there needs to be stringent regulation of the release of heavy metals into the environment.
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An extended class of organic multi-redox systems was derived from bicyclic(alkyl)amino carbenes (BICAACs). The highly-conjugated system undergoes a total of 4 redox events spanning a 1.8â V redox range. These organic compounds exhibited four different stable redox states (dication, radical cation, neutral and radical anion), and all of them were characterized either by single crystal X-ray study and/or various spectroscopic studies. Three of the four redox states are stable to air and moisture. The availability of stable multiple redox states demonstrated promise towards their efficacy in the symmetric H-cell charge/discharge cycling. Among various redox states, the dication/neutral state works efficiently and continuously for 1500 cycles in 2e- charge/discharge process outside glovebox in commercially available DMF with minimum capacity loss (retaining nearly 90 % Coulombic efficiency). Surprisingly, the efficiency of the redox cycle was retained even if the system was exposed to air for 30â days when it slowly regenerated to the initial deep blue radical cation, and it exhibited another 100 charge/discharge cycles with a minimal capacity loss. Such a stable H-cell cycling ability is not well known among organic molecule-based systems.
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Natural products are attractive components to tailor environmentally friendly advanced new materials. We present surface-confined metallosupramolecular engineering of coordination polymers using natural dyes as molecular building blocks: indigo and the related Tyrian purple. Both building blocks yield identical, well-defined coordination polymers composed of (1 dehydroindigo : 1 Fe) repeat units on two different silver single crystal surfaces. These polymers are characterized atomically by submolecular resolution scanning tunnelling microscopy, bond-resolving atomic force microscopy and X-ray photoelectron spectroscopy. On Ag(100) and on Ag(111), the trans configuration of dehydroindigo results in N,O-chelation in the polymer chains. On the more inert Ag(111) surface, the molecules additionally undergo thermally induced isomerization from the trans to the cis configuration and afford N,N- plus O,O-chelation. Density functional theory calculations confirm that the coordination polymers of the cis-isomers on Ag(111) and of the trans-isomers on Ag(100) are energetically favoured. Our results demonstrate post-synthetic linker isomerization in interfacial metal-organic nanosystems.
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In addition to the discovery of new (modified) potent antibiotics to combat antibiotic resistance, there is a critical need to develop novel strategies that would restrict their off-target effects and unnecessary exposure to bacteria in our body and environment. We report a set of new photoswitchable arylazopyrazole-modified norfloxacin antibiotics that present a high degree of bidirectional photoisomerization, impressive fatigue resistance and reasonably high cis half-lives. The irradiated isomers of most compounds were found to exhibit nearly equal or higher antibacterial activity than norfloxacin against Gram-positive bacteria. Notably, against norfloxacin-resistant S.â aureus bacteria, the visible-light-responsive p-SMe-substituted derivative showed remarkably high antimicrobial potency (MIC of 0.25â µg/mL) in the irradiated state, while the potency was reduced by 24-fold in case of its non-irradiated state. The activity was estimated to be retained for more than 7â hours. This is the first report to demonstrate direct photochemical control of the growth of antibiotic-resistant bacteria and to show the highest activity difference between irradiated and non-irradiated states of a photoswitchable antibiotic. Additionally, both isomers were found to be non-harmful to human cells. Molecular modellings were performed to identify the underlying reason behind the high-affinity binding of the irradiated isomer to topoisomerase IV enzyme.
Subject(s)
Anti-Infective Agents , Methicillin-Resistant Staphylococcus aureus , Humans , Anti-Bacterial Agents/pharmacology , Norfloxacin/pharmacology , Bacteria , Anti-Infective Agents/pharmacology , Microbial Sensitivity TestsABSTRACT
Photopharmacology holds huge potential for the permanent (long-term) eradication of antibiotic resistance by the application of photoswitchable antibiotics. To construct such antibiotics, various methods have been employed to modify known antibiotics with photoswitches, such that the irradiated state shows activity comparable to or higher than that of the parent antibiotic and that a large activity difference between irradiated and nonirradiated states is achieved. However, most of those methods are ineffective when dealing with more than one drug with dissimilar structures. Here, we have demonstrated a new approach, in which two pharmacophores, one being a photoswitch, are covalently linked via a spacer of variable lengths, leading to a set of azopyrazole-norfloxacin antibiotic hybrids. All compounds showed a high degree of bidirectional photoisomerization, long thermal cis half-lives, and excellent photoresistance. Notably, the hybrid with an optimal four-carbon spacer length enabled the irradiated state to become 12-fold more potent than its nonirradiated state without losing much antimicrobial activity of norfloxacin. Only Gram-positive bacteria were found to be sensitive to this hybrid, and the full antibacterial potency of its irradiated state was found to be retained for nearly 24 h.
Subject(s)
Anti-Bacterial Agents , Norfloxacin , Anti-Bacterial Agents/chemistry , Norfloxacin/pharmacology , Gram-Positive BacteriaABSTRACT
We use Floquet formalism to study fluctuations in periodically modulated continuous quantum thermal machines. We present a generic theory for such machines, followed by specific examples of sinusoidal, optimal, and circular modulations, respectively. The thermodynamic uncertainty relations (TUR) hold for all modulations considered. Interestingly, in the case of sinusoidal modulation, the TUR ratio assumes a minimum at the heat engine to refrigerator transition point, while the chopped random basis optimization protocol allows us to keep the ratio small for a wide range of modulation frequencies. Furthermore, our numerical analysis suggests that TUR can show signatures of heat engine to refrigerator transition, for more generic modulation schemes. We also study bounds in fluctuations in the efficiencies of such machines; our results indicate that fluctuations in efficiencies are bounded from above for a refrigerator and from below for an engine. Overall, this study emphasizes the crucial role played by different modulation schemes in designing practical quantum thermal machines.
ABSTRACT
Azopyrazoles are an emerging class of photoswitches, whereas analogous azoimidazole-based switches are unable to draw much attention because of their short cis half-lives, poor cis-trans photoreversion yields, and toxic ultraviolet (UV) light-assisted isomerization. A series of 24 various aryl-substituted N-methyl-2-arylazoimidazoles were synthesized, and their photoswitching performances and cis-trans isomerization kinetics were thoroughly investigated experimentally and theoretically. Para-π-donor-substituted azoimidazoles with highly twisted T-shaped cis conformations showed nearly complete bidirectional photoswitching, whereas di-o-substituted switches exhibited very long cis half-lives (days-years) with nearly ideal T-shaped conformations. This study demonstrates how the electron density in the aryl ring affects cis half-life and cis-trans photoreversion via twisting of the NNAr dihedral angle that can be used as a predictive metric for envisaging and tuning the likely switching performance and half-life of any given 2-arylazoimidazole. By applying this tool, two better-performing azoimidazole photoswitches were engineered. All switches permitted irradiation by violet (400-405 nm) and orange (>585 nm) light for forward and reverse isomerization, respectively, and displayed comparatively high quantum yields and impressive resistance to photobleaching.
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Recent advances in spatial transcriptomics (ST) have allowed for the mapping of tissue heterogeneity, but this technique lacks the resolution to investigate gene expression patterns, cell-cell communications and tissue organization at the single-cell resolution. ST data contains a mixed transcriptome from multiple heterogeneous cells, and current methods predict two-dimensional (2D) coordinates for individual cells within a predetermined space, making it difficult to reconstruct and study three-dimensional (3D) tissue organization. Here we present a new computational method called scHolography that uses deep learning to map single-cell transcriptome data to 3D space. Unlike existing methods, which generate a projection between transcriptome data and 2D spatial coordinates, scHolography uses neural networks to create a high-dimensional transcriptome-to-space map that preserves the distance information between cells, allowing for the construction of a cell-cell proximity matrix beyond the 2D ST scaffold. Furthermore, the neighboring cell profile of a given cell type can be extracted to study spatial cell heterogeneity. We apply scHolography to human skin, human skin cancer and mouse brain datasets, providing new insights into gene expression patterns, cell-cell interactions and spatial microenvironment. Together, scHolography offers a computational solution for digitizing transcriptome and spatial information into high-dimensional data for neural network-based mapping and the reconstruction of 3D tissue organization at the single-cell resolution.
ABSTRACT
The self-assembly of a carboxylate-based dinucleating ligand, N,N'-bis[2-carboxybenzomethyl]-N,N'-bis[2-pyridylmethyl]-1,3-diaminopropan-2-ol (H3cpdp), and copper(II) ions in the presence of various exogenous ancillary ligands results in the formation of the new dinuclear complex [Cu2(cpdp)(µ-Hisophth)]4·2H2isophth·21H2O (1), trinuclear complex [Cu3(Hcpdp)(Cl)4] (2), and tetranuclear complex [Cu4(cpdp)(µ-Hphth)(µ4-phth)(piconol)(Cl)2]·3H2O (3) (H2phth = phthalic acid; H2isophth = isophthalic acid; piconol = 2-pyridinemethanol; Cl- = chloride). In methanol-water, the reaction of H3cpdp with CuCl2·2H2O at room temperature leads to the formation of 2. On the other hand, 1 and 3 have been obtained by carrying out the reaction of H3cpdp with CuCl2·2H2O/m-C6H4(CO2Na)2 and CuCl2·2H2O/o-C6H4(CO2Na)2/piconol, respectively, in methanol-water in the presence of NaOH at ambient temperature. All three complexes have been characterized by elemental analysis, molar electrical conductivity and magnetic moment measurements, FTIR, UV-vis spectroscopy, and PXRD, including single-crystal X-ray structural analyses. The molecular structure of 1 is based on a µ-alkoxide and µ-isophthalate-bridged dimeric [Cu2] core; the structure of 2 represents a trimeric [Cu3] core in which a µ-alcohol-bridged dinuclear [Cu2] unit is exclusively coupled with a [CuCl2] species by two µ:η1:η1-syn-anti carboxylate groups forming a triangular motif; the structure of 3 embodies a tetrameric [Cu4] core, with two copper(II) ions in a distorted-octahedral coordination environment, one copper(II) ion in a distorted-trigonal-bipyramidal coordination environment, and the other copper(II) ion in a square-planar coordination environment. In fact, 2 and 3 represent rare examples of copper(II)-based multinuclear complexes showing outstanding features of rich coordination chemistry: (i) using a symmetrical dinucleating ligand, trinuclear complex 2 is generated with four- and five-coordination environments around copper(II) ions; (ii) the unsymmetrical tetranuclear complex 3 is obtained by using the same ligand with four-, five- and six-coordination environments around copper(II) ions; (iii) tetracopper(II) complex 3 shows four different bridging modes of carboxylate groups simultaneously such as µ:η2, µ:η1:η1, µ3:η2:η1:η1, and µ4:η1:η1:η1:η1, the µ4:η1:η1:η1:η1 mode of phthalate being unprecedented. The formation of these [Cu2], [Cu3], and [Cu4] complexes can be controlled by changing the exogenous ancillary ligands and pH of the reaction solutions, thus allowing an effective tuning of the self-assembly. The magnetic susceptibility measurements suggest that the copper centers in all three complexes are antiferromagnetically coupled. The thermal properties of 1-3 have been investigated by thermogravimetric and differential thermal analytical (TGA and DTA) techniques, indicating that the decomposition of all three complexes proceeds via multistep processes.
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An extended class of stable mesoionic N-heterocyclic imines (mNHIs), containing a highly polarized exocyclic imine moiety, were synthesized. The calculated proton affinities (PA) and experimentally determined Tolman electronic parameters (TEPs) reveal that these synthesized mNHIs have the highest basicity and donor ability among NHIs reported so far. The superior nucleophilicity of newly designed mNHIs was utilized in devising a strategy to incorporate CO2 as a bridging unit under reductive conditions to couple inert primary amides. This strategy was further extended to hetero-couplings between amide and amine using CO2 . These hitherto unknown catalytic transformations were introduced in the diversification of various biologically active drug molecules under metal-free conditions. The underlying mechanism was explored by performing a series of control experiments, characterizing key intermediates using spectroscopic and crystallographic techniques.
Subject(s)
Amides , Imines , Imines/chemistry , Amides/chemistry , Carbon Dioxide/chemistry , Catalysis , Amines/chemistryABSTRACT
Herein, we report the synthesis of a benzimidazolylidene-stabilized borane adduct and its borenium ion. This borenium ion was used as a metal-free catalyst for hydrogenating various substituted quinoline N-heterocycles under ambient conditions. Furthermore, this method was utilized to synthesize two drug molecules: galipinine and angustureine. A detailed DFT study was performed to understand this metal-free catalytic hydrogenation.
Subject(s)
Boranes , Catalysis , HydrogenationABSTRACT
The use of platinum (Pt)-based anticancer drugs, although widespread in clinical practice, is severely limited due to toxic side-effects. One of the strategies for making Pt-based chemotherapy more effective is the synthesis and use of Pt nanoparticles (PtNPs). However, increasing evidence suggestD that nanoplatinum also pose potential risk to human health. This study examined the toxicity and anticancer activity of mycosynthesized PtNPs against sarcoma-180 (S-180) cells in vitro and in vivo. Curvularia affinis Boedijn, a phyto-pathogenic fungi isolated from rice, was used to synthesize PtNPs (named as CaPtNP). Well dispersed, mostly spherical CaPtNPs, with sizes ranging from 3-9 nm were characterized by Transmission electron microscopy (TEM), field emission scanning electron microscopy, X-ray diffraction, atomic force microscopy, and Fourier transform infrared spectrometry. Two concentrations of the CaPtNPs (2.31 and 4.63 ng/mL) were selected based on in vitro cytotoxicity assay on erythrocytes and peripheral blood mononuclear cells. The selected doses were found to induce significant in vitro and in vivo anti-proliferative and pro-apoptotic activity in S-180 cells. Elevated levels of pro-apoptotic markers (p53, Bax/Bcl2 ratio, Cyt c, caspase-3, cleaved PARP) and reduced BrdU incorporation validated the anticancer activity of CaPtNPs. The antitumor activity was further confirmed in S-180 transplanted tumor bearing mice. Moreover, examination of the impact of sub-chronic exposure (three months) of CaPtNPs on the ultra-structural features of renal and hepatic tissue by TEM revealed no significant toxicological manifestation in these organs. The CaPtNPs were also found to reduce oxidative stress and improve liver function in tumor bearing mice compared with untreated controls. Thus, this green CaPtNPs was well tolerated in mice and displayed significant antitumor property.
Subject(s)
Antineoplastic Agents , Metal Nanoparticles , Animals , Antineoplastic Agents/pharmacology , Curvularia , Humans , Leukocytes, Mononuclear , Mice , Platinum/chemistry , Platinum/pharmacology , Spectroscopy, Fourier Transform InfraredABSTRACT
Herein we report the first metal-free regioselective Markovnikov ring-opening of epoxides (selectivity up to 99%) using an abnormal N-heterocyclic carbene (aNHC) to yield secondary alcohols. DFT calculations and X-ray crystallography suggest that the Markovnikov selectivity originates from the high nucleophilicity and steric factors associated with the aNHC.
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Background: Blood flow restriction (BFR) training at lower exercise intensities has a range of applications, allowing subjects to achieve strength and hypertrophy gains matching those training at high intensity. However, there is no clear consensus on the percentage of limb occlusion pressure [%LOP, expressed as a % of the pressure required to occlude systolic blood pressure (SBP)] and percentage of one repetition max weight (%1RM) required to achieve these results. This review aims to explore what the optimal and minimal combination of LOP and 1RM is for significant results using BFR. Method: A literature search using PubMed, Scopus, Wiley Online, Springer Link, and relevant citations from review papers was performed, and articles assessed for suitability. Original studies using BFR with a resistance training exercise intervention, who chose a set %LOP and %1RM and compared to a non-BFR control were included in this review. Result: Twenty-one studies met the inclusion criteria. %LOP ranged from 40 to 150%. %1RM used ranged from 15 to 80%. Training at 1RM ≤20%, or ≥ 80% did not produce significant strength results compared to controls. Applying %LOP of ≤50% and ≥ 80% did not produce significant strength improvement compared to controls. This may be due to a mechanism mediated by lactate accumulation, which is facilitated by increased training volume and a moderate exercise intensity. Conclusion: Training at a minimum of 30 %1RM with BFR is required for strength gains matching non-BFR high intensity training. Moderate intensity training (40-60%1RM) with BFR may produce results exceeding non-BFR high intensity however the literature is sparse. A %LOP of 50-80% is optimal for BFR training.
ABSTRACT
We discuss a model of a closed quantum evolution of two qubits where the joint Hamiltonian is so chosen such that one of the qubits acts as a bath and thermalizes the other qubit which is acting as the system. The corresponding exact master equation for the system is derived. Interestingly, for a specific choice of parameters the master equation takes the Gorini-Kossakowski-Lindblad-Sudarshan (GKLS) form, with constant coefficients representing pumping and damping of a single qubit system. Based on this model we construct an Otto cycle connected to a single qubit bath and study its thermodynamic properties. Our analysis goes beyond the conventional weak coupling scenario and illustrates the effects of finite baths, including non-Markovianity. We find closed form expressions for efficiency (coefficient of performance), power (cooling power) for the heat engine regime (refrigerator regime), and for different modifications of the joint Hamiltonian.
Subject(s)
Cold Temperature , Hot Temperature , Phase Transition , ThermodynamicsABSTRACT
Correction for 'Redox-active ligand based Mn(I)-catalyst for hydrosilylative ester reduction' by Soumi Chakraborty et al., Chem. Commun., 2021, 57, 12671-12674, DOI: 10.1039/D1CC05614J.
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In this paper, we analyze the classical capacity of the generalized Pauli channels generated via memory kernel master equations. For suitable engineering of the kernel parameters, evolution with non-local noise effects can produce dynamical maps with a higher capacity than a purely Markovian evolution. We provide instructive examples for qubit and qutrit evolution. Interestingly, similar behavior is not observed when analyzing time-local master equations.