Complementary supramolecular drug associates in perfecting the multidrug therapy against multidrug resistant bacteria.

The inappropriate and inconsistent use of antibiotics in combating multidrug-resistant bacteria exacerbates their drug resistance through a few distinct pathways. Firstly, these bacteria can accumulate multiple genes, each conferring resistance to a specific drug, within a single cell. This accumulation usually takes place on resistance plasmids (R). Secondly, multidrug resistance can arise from the heightened expression of genes encoding multidrug efflux pumps, which expel a broad spectrum of drugs from the bacterial cells. Additionally, bacteria can also eliminate or destroy antibiotic molecules by modifying enzymes or cell walls and removing porins. A significant limitation of traditional multidrug therapy lies in its inability to guarantee the simultaneous delivery of various drug molecules to a specific bacterial cell, thereby fostering incremental drug resistance in either of these paths. Consequently, this approach prolongs the treatment duration. Rather than using a biologically unimportant coformer in forming cocrystals, another drug molecule can be selected either for protecting another drug molecule or, can be selected for its complementary activities to kill a bacteria cell synergistically. The development of a multidrug cocrystal not only improves tabletability and plasticity but also enables the simultaneous delivery of multiple drugs to a specific bacterial cell, philosophically perfecting multidrug therapy. By adhering to the fundamental tenets of multidrug therapy, the synergistic effects of these drug molecules can effectively eradicate bacteria, even before they have the chance to develop resistance. This approach has the potential to shorten treatment periods, reduce costs, and mitigate drug resistance. Herein, four hypotheses are presented to create complementary drug cocrystals capable of simultaneously reaching bacterial cells, effectively destroying them before multidrug resistance can develop. The ongoing surge in the development of novel drugs provides another opportunity in the fight against bacteria that are constantly gaining resistance to existing treatments. This endeavour holds the potential to combat a wide array of multidrug-resistant bacteria.

Cocrystallizing and Codelivering Complementary Drugs to Multidrugresistant Tuberculosis Bacteria in Perfecting Multidrug Therapy.

Bacteria cells exhibit multidrug resistance in one of two ways: by raising the genetic expression of multidrug efflux pumps or by accumulating several drug-resistant components in many genes. Multidrug-resistive tuberculosis bacteria are treated by multidrug therapy, where a few certain antibacterial drugs are administered together to kill a bacterium jointly. A major drawback of conventional multidrug therapy is that the administration never ensures the reaching of different drug molecules to a particular bacterium cell at the same time, which promotes growing drug resistivity step-wise. As a result, it enhances the treatment time. With additional tabletability and plasticity, the formation of a cocrystal of multidrug can ensure administrating the multidrug chemically together to a target bacterium cell. With properly maintaining the basic philosophy of multidrug therapy here, the synergistic effects of drug molecules can ensure killing the bacteria, even before getting the option to raise the drug resistance against them. This can minimize the treatment span, expenditure and drug resistance. A potential threat of epidemic from tuberculosis has appeared after the Covid-19 outbreak. An unwanted loop of finding molecules with the potential to kill tuberculosis, getting their corresponding drug approvals, and abandoning the drug after facing drug resistance can be suppressed here. This perspective aims to develop the universal drug regimen by postulating the principles of drug molecule selection, cocrystallization, and subsequent harmonisation within a short period to address multidrug-resistant bacteria.

An Inbuilt Electronic Pawl Gates Orbital Information Processing and Controls the Rotation of a Double Ratchet Rotary Motor.

A direct external input energy source (e.g., light, chemical reaction, redox potential, etc.) is compulsory to supply energy to rotary motors for accomplishing rotation around the axis. The stator leads the direction of rotation, and a sustainable rotation requires two mutual input energy supplies (e.g., light and heat, light and pH or metal ion, etc.); however, there are some exceptions (e.g., covalent single bond rotors and/or motors). On the contrary, our experiment suggested that double ratchet rotary motors (DRMs) can harvest power from available thermal noise, kT, for sustainable rotation around the axis. Under a scanning tunneling microscope, we have imaged live thermal noise movement as a dynamic orbital density and resolved the density diagram up to the second derivative. A second input energy can synchronize multiple rotors to afford a measurable output. Therefore, we hypothesized that rotation control in a DRM must be evolved from an orbital-level information transport channel between the two coupled rotors but was not limited to the second input energy. A DRM comprises a Brownian rotor and a power stroke rotor coupled to a -C≡C- stator, where the transport of information through coupled orbitals between the two rotors is termed the vibrational information flow chain (VIFC). We test this hypothesis by studying the DRM's density functional theory calculation and variable-temperature 1H nuclear magnetic resonance. Additionally, we introduced inbuilt pawl-like functional moieties into a DRM to create different electronic environments by changing proton intercalation interactions, which gated information processing through the VIFC. The results show the VIFC can critically impact the motor's noise harvesting, resulting in variable rotational motions in DRMs.

Hydrogen-producing Photocatalyst at Sunscreen for Athletes in Preventing and Healing Muscle-nerve-skin Injuries.

Physical injuries in sports are unavoidable, but they can be mitigated and even treated by using molecular hydrogen, which can be administered via a specially formulated sunscreen. The photocatalysts are a special class of semiconductors that can absorb a specific spectrum of light to promote its electron from the valance band (VB) to the conduction band (CB). This creates positively charged holes at VB and negatively charged electrons at CB in generating photochemical reaction centres. Once a photocatalyst that absorbs a harmful UV band from sunlight and can split water is doped inside a hydrogel will produce hydrogen in the presence of sunlight. If we employ such photocatalyst-doped hydrogel over naked skin, the hydrogel will act as a continuous source of water, which will absorb water from sweet, store it inside the hydrogel matrix and deliver it to the photocatalyst for splitting it further into the hydrogen. As a result, such photocatalyst-doped hydrogel can be used as a sunscreen to protect against sunlight and can use that spectrum of light for producing hydrogen from sweat continuously. Hydrogen can be absorbed through the skin and diffused in the body to heal wound-prone or injured muscles, and nerves. Because hydrogen may travel throughout the body, the catalyst-doped hydrogel can be used as a topical gel to treat various ailments such as muscle-nerve skin injuries, cancer, Parkinson's disease, and others. Besides common people, even athletes can use it as sunscreen during sports, which is not feasible for other hydrogen administrating systems.

The century-old picture of a nerve spike is wrong: filaments fire, before membrane.

In 1907, Lapicque proposed that an electric field passes through the neuronal membrane and transmits a signal. Subsequently, a "snake curve" or spike was used to depict the means by which a linear flat current undergoes a sudden Gaussian or Laplacian peak. This concept has been the accepted scenario for more than 115 years even appearing in textbooks on the subject. It was not noted that the membrane spike should have a cylindrical shape. A nerve spike having a dot shape on membrane surface cannot propagate through a cylindrical surface since it would dissipate instantaneously. A nerve spike should have the appearance of a ring, encompassing the diameter of a cylindrical axon or dendron. However, this subtle change has remarkable implications. Maintaining a circular form of an electric field is not easy, especially at the surface of an organic object. Here, we suggest that neuroscience could redefine itself if we accept that a nerve spike is not a localized 3D Gaussian or Laplacian wave packet, rather it is a 3D ring encompassing the diameter of a neural branch.

Electrophysiology using coaxial atom probe array: live imaging reveals hidden circuits of a hippocampal neural network.

Since the 1960s, it is held that when a neuron fires, a nerve spike passes only through the selective branches, the calculated choice is a key to learning by rewiring. It is argued by chemically estimating the membrane's ion channel density that different axonal branches get active to pass the spike-branches blink at firing at different time domains. Here, using a new time-lapse dielectric imaging, we visualize the classic branch selection process; thenceforth, hidden circuits operating at different time domains become visible. The fractal grid of coaxial probes captures wireless snapshots of material's vibration at various depths below the membrane by setting a suitable frequency. Thus far, branch selection observed emitted energy or particle but never the emitters, what they do. As each dielectric material transmits and reflects signals of different frequencies, we image live how filaments search for many branch-made circuits, choose a unique pathway 103 times faster than a single nerve spike. It reveals that neural branches and circuit visible in a microscope are not absolute, there coexist many circuits each operating in different dime domains, operating at a time.NEW & NOTEWORTHY Using dielectric resonance scanner, we show electromagnetic field connections between physically separated neurons. Electromagnetic field creates field lines that pass through gap junctions, connect Axon initial segment with the dendrites through Soma, and connect axonal or dendritic branches even if there is no synaptic junction. Consequently, many distinct loops connecting various branches form coexisting circuits. Our discovery suggests that physically appearing neural circuit is a fractional view of many simultaneously operating circuits in different time domains in a neural network.

Correction: Speedy one-pot electrochemical synthesis of giant octahedrons from in situ generated pyrrolidinyl PAMAM dendrimer.

Correction for 'Speedy one-pot electrochemical synthesis of giant octahedrons from in situ generated pyrrolidinyl PAMAM dendrimer' by Anup Singhania et al., Soft Matter, 2020, 16, 9140-9146, DOI: 10.1039/D0SM00819B.

Filaments and four ordered structures inside a neuron fire a thousand times faster than the membrane: theory and experiment.

The current action potential paradigm considers that all components beneath the neuron membrane are inconsequential. Filamentary communication is less known to the ionic signal transmission; recently, we have proposed that the two are intimately linked through time domains. We modified the atom probe-connected dielectric resonance scanner to operate in two-time domains, milliseconds and microseconds simultaneously for the first time. We resonate the ions for imaging rather than neutralizing them as patch clamps do; resonant transmission images the ion flow 103 times faster than the existing methods. We revisited action potential-related events by scanning in and around the axon initial segment (AIS). Four ordered structures in the cytoskeletal filaments exchange energy ~250 µs before a neuron fires, editing spike-time-gap-key to the brain's cognition. We could stop firing above a threshold or initiate a fire by wirelessly pumping electromagnetic signals. We theoretically built AIS, whose simulated electromagnetic energy exchange matched the experiment. Thus far, the scanner could detect & link uncorrelated biological events unfolding over 106 orders in the time scale simultaneously. Our experimental findings support a new dielectric resonator model of neuron functioning in various time domains, thus suggesting the dynamic anatomy of electrical activity as information-rich.

Speedy one-pot electrochemical synthesis of giant octahedrons from in situ generated pyrrolidinyl PAMAM dendrimer.

A novel electrochemical synthesis via a radical generation pathway is described here for the generation of a quaternary megamer structure from secondary dendrimers. The reaction is rapid and completes in <5 min. We have used lower/higher generation poly(amido)amine (PAMAM) dendrimers with carboxylic acid groups at the terminals. A precise electrocatalytic reaction at >3.5 V activates the carboxylic groups to undergo anodic oxidation (-e-) and produce radical carboxylate anions on the dendrimer surface. The reaction further goes through a decarboxylative elimination. Successive self-assembly creates billions of polydispersed and extremely stable ∼500 nm octahedron nanostructures, which we failed to destroy even by using a 20 kV electron beam. This is a new route for the speedy synthesis of important futuristic materials of well-defined shape. It has applications in building designer organic crystals for solar cells, organic electronics, rapid protein gelation, rapid protein crystallization, etc.

Radio Waveguide-Double Ratchet Rotors Work in Unison on a Surface to Convert Heat into Power.

Synchronizing thousands of 100% efficient rotors in a macrodevice for harvesting noise is unapprehended. Thermodynamically, realizing a thermal gradient at the atomic scale is critical. Harvesting free thermal energy or noise by resonance has a hidden clause; either externally activating a directed self-powered motion or constructing a nanoscale power supply. To accomplish this, we combined two rotor concepts, Brownian rotor, BR, and power stroke, PS, rotors available in living systems in two planes of a single molecule. Quantum tunneling images reveal how a radio-wave guided synchronization of PS-BR combination tweaks rotational dynamics of a rotor to bypass the necessity of temperature gradient (ΔT). Live imaging of thermal noise movement as electron density between a pair of molecular planes helped in optimizing the rotor design. The rotor's monolayer harvests heat from the liquid's Brownian noise and electromagnetic noise, together delivering a finite, usable power. The chip supplies the power if we wet the surface or shine electric noise.

Electrocatalytic water oxidation by Cu(ii) ions in a neutral borate buffer solution.

Herein we report that a Cu(ii) salt can efficiently catalyze water oxidation in a neutral borate buffer. Studies on the mechanism revealed that the borate anion serves as an oxygen donor in O-O bond formation during the process of water oxidation, assisting in enhancing the catalytic activity of Cu(ii).

Rapid exchange between atmospheric CO2 and carbonate anion intercalated within magnesium rich layered double hydroxide.

The carbon cycle, by which carbon atoms circulate between atmosphere, oceans, lithosphere, and the biosphere of Earth, is a current hot research topic. The carbon cycle occurring in the lithosphere (e.g., sedimentary carbonates) is based on weathering and metamorphic events so that its processes are considered to occur on the geological time scale (i.e., over millions of years). In contrast, we have recently reported that carbonate anions intercalated within a hydrotalcite (Mg0.75Al0.25(OH)2(CO3)0.125·yH2O), a class of a layered double hydroxide (LDH), are dynamically exchanging on time scale of hours with atmospheric CO2 under ambient conditions. (Ishihara et al., J. Am. Chem. Soc. 2013, 135, 18040-18043). The use of (13)C-labeling enabled monitoring by infrared spectroscopy of the dynamic exchange between the initially intercalated (13)C-labeled carbonate anions and carbonate anions derived from atmospheric CO2. In this article, we report the significant influence of Mg/Al ratio of LDH on the carbonate anion exchange dynamics. Of three LDHs of various Mg/Al ratios of 2, 3, or 4, magnesium-rich LDH (i.e., Mg/Al ratio = 4) underwent extremely rapid exchange of carbonate anions, and most of the initially intercalated carbonate anions were replaced with carbonate anions derived from atmospheric CO2 within 30 min. Detailed investigations by using infrared spectroscopy, scanning electron microscopy, powder X-ray diffraction, elemental analysis, adsorption, thermogravimetric analysis, and solid-state NMR revealed that magnesium rich LDH has chemical and structural features that promote the exchange of carbonate anions. Our results indicate that the unique interactions between LDH and CO2 can be optimized simply by varying the chemical composition of LDH, implying that LDH is a promising material for CO2 storage and/or separation.

Dynamic breathing of CO2 by hydrotalcite.

The carbon cycle of carbonate solids (e.g., limestone) involves weathering and metamorphic events, which usually occur over millions of years. Here we show that carbonate anion intercalated layered double hydroxide (LDH), a class of hydrotalcite, undergoes an ultrarapid carbon cycle with uptake of atmospheric CO2 under ambient conditions. The use of (13)C-labeling enabled monitoring by IR spectroscopy of the dynamic exchange between initially intercalated (13)C-labeled carbonate anions and carbonate anions derived from atmospheric CO2. Exchange is promoted by conditions of low humidity with a half-life of exchange of ~24 h. Since hydrotalcite-like clay minerals exist in Nature, our finding implies that the global carbon cycle involving exchange between lithosphere and atmosphere is much more dynamic than previously thought.

Naked-eye discrimination of methanol from ethanol using composite film of oxoporphyrinogen and layered double hydroxide.

Methanol is a highly toxic substance, but it is unfortunately very difficult to differentiate from other alcohols (especially ethanol) without performing chemical analyses. Here we report that a composite film prepared from oxoporphyrinogen (OxP) and a layered double hydroxide (LDH) undergoes a visible color change (from magenta to purple) when exposed to methanol, a change that does not occur upon exposure to ethanol. Interestingly, methanol-induced color variation of the OxP-LDH composite film is retained even after removal of methanol under reduced pressure, a condition that does not occur in the case of conventional solvatochromic dyes. The original state of the OxP-LDH composite film could be recovered by rinsing it with tetrahydrofuran (THF), enabling repeated usage of the composite film. The mechanism of color variation, based on solid-state (13)C-CP/MAS NMR and solution-state (13)C NMR studies, is proposed to be anion transfer from LDH to OxP triggered by methanol exposure.

Gel sculpture: moldable, load-bearing and self-healing non-polymeric supramolecular gel derived from a simple organic salt.

An easy access to a library of simple organic salts derived from tert-butoxycarbonyl (Boc)-protected L-amino acids and two secondary amines (dicyclohexyl- and dibenzyl amine) are synthesized following a supramolecular synthon rationale to generate a new series of low molecular weight gelators (LMWGs). Out of the 12 salts that we prepared, the nitrobenzene gel of dicyclohexylammonium Boc-glycinate (GLY.1) displayed remarkable load-bearing, moldable and self-healing properties. These remarkable properties displayed by GLY.1 and the inability to display such properties by its dibenzylammonium counterpart (GLY.2) were explained using microscopic and rheological data. Single crystal structures of eight salts displayed the presence of a 1D hydrogen-bonded network (HBN) that is believed to be important in gelation. Powder X-ray diffraction in combination with the single crystal X-ray structure of GLY.1 clearly established the presence of a 1D hydrogen-bonded network in the xerogel of the nitrobenzene gel of GLY.1. The fact that such remarkable properties arising from an easily accessible (salt formation) small molecule are due to supramolecular (non-covalent) interactions is quite intriguing and such easily synthesizable materials may be useful in stress-bearing and other applications.

Supramolecular synthons in designing low molecular mass gelling agents: L-amino acid methyl ester cinnamate salts and their anti-solvent-induced instant gelation.

Easy access to a class of chiral gelators has been achieved by exploiting primary ammonium monocarboxylate (PAM), a supramolecular synthon. A combinatorial library comprising of 16 salts, derived from 5 L-amino acid methyl esters and 4 cinnamic acid derivatives, has been prepared and scanned for gelation. Remarkably, 14 out of 16 salts prepared (87.5 % of the salts) show moderate to good gelation abilities with various solvents, including commercial fuels, such as petrol. Anti-solvent induced instant gelation at room temperature has been achieved in all the gelator salts, indicating that the gelation process is indeed an aborted crystallization phenomenon. Rheology, optical and scanning electron microscopy, small angle neutron scattering, and X-ray powder diffraction have been used to characterize the gels. A structure-property correlation has been attempted, based on these data, in addition to the single-crystal structures of 5 gelator salts. Analysis of the FT-IR and (1)H NMR spectroscopy data reveals that some of these salts can be used as supramolecular containers for the slow release of certain pest sex pheromones. The present study clearly demonstrates the merit of crystal engineering and the supramolecular synthon approach in designing new materials with multiple properties.

Combinatorial library of primaryalkylammonium dicarboxylate gelators: a supramolecular synthon approach.

Following the supramolecular synthon approach, a combinatorial library comprising 35 organic salts derived from 7 dicarboxylic acids (malonic-, succinic-, adipic-, L-tartaric-, maleic-, phthalic-, and isophthalicacid) and 5 primaryalkyl amines Me-(CH2)n-NH2 (n = 11-15) was prepared and scanned for gelation. About 66% of the salts in the combinatorial library were found to show moderate to good gelling ability in various polar and nonpolar solvents including commercial fuels such as petrol. The majority of the salts having a rigid, unsaturated anionic backbone (maleate, phthalate, and isophthalate) did not show gelation; only the corresponding hexadecylammonium salts showed gelation. Some of the representative gels were characterized by rheology, small-angle neutron scattering (SANS), optical microscopy (OM), and scanning electron microscopy (SEM). Single-crystal structures of two gelator and two nongelator salts were also discussed in the context of supramolecular synthon and structure-property correlation.