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Nicotinic acetylcholine receptors are ligand-gated ion channels that mediate fast chemical neurotransmission; here, the first X-ray crystal structure of a nicotinic receptor is reported, revealing how nicotine stabilizes the receptor in a non-conducting, desensitized conformation. Structure of a nicotinic acetylcholine receptor Nicotinic acetylcholine receptors are ligand-gated ion channels that mediate fast chemical neurotransmission at the neuromuscular junction and have diverse signalling roles in the central nervous system. In this manuscript, the authors report the first X-ray crystal structure of the human α4β2 nicotinic receptor, the most abundant nicotinic subtype in the brain. In addition to representing the first high-resolution structure of a heteromeric member of the pentameric 'Cys-loop' receptor family, the structure was obtained in the presence of nicotine and reveals how this agonist stabilizes the receptor in a non-conducting, desensitized conformation. Nicotinic acetylcholine receptors are ligand-gated ion channels that mediate fast chemical neurotransmission at the neuromuscular junction and have diverse signalling roles in the central nervous system. The nicotinic receptor has been a model system for cell-surface receptors, and specifically for ligand-gated ion channels, for well over a century 1 , 2 . In addition to the receptors’ prominent roles in the development of the fields of pharmacology and neurobiology, nicotinic receptors are important therapeutic targets for neuromuscular disease, addiction, epilepsy and for neuromuscular blocking agents used during surgery 2 , 3 , 4 . The overall architecture of the receptor was described in landmark studies of the nicotinic receptor isolated from the electric organ of Torpedo marmorata 5 . Structures of a soluble ligand-binding domain have provided atomic-scale insights into receptor–ligand interactions 6 , while high-resolution structures of other members of the pentameric receptor superfamily provide touchstones for an emerging allosteric gating mechanism 7 . All available high-resolution structures are of homopentameric receptors. However, the vast majority of pentameric receptors (called Cys-loop receptors in eukaryotes) present physiologically are heteromeric. Here we present the X-ray crystallographic structure of the human α4β2 nicotinic receptor, the most abundant nicotinic subtype in the brain. This structure provides insights into the architectural principles governing ligand recognition, heteromer assembly, ion permeation and desensitization in this prototypical receptor class.

The development of efficient methods, particularly catalytic and enantioselective processes, for the construction of all-carbon quaternary stereocentres is an important (and difficult) challenge in organic synthesis due to the occurrence of this motif in a range of bioactive molecules. One conceptually straightforward and potentially versatile approach is the catalytic enantioconvergent substitution reaction of a readily available racemic tertiary alkyl electrophile by an organometallic nucleophile; however, examples of such processes are rare. Here we demonstrate that a nickel-based chiral catalyst achieves enantioconvergent couplings of a variety of tertiary electrophiles (cyclic and acyclic α-halocarbonyl compounds) with alkenylmetal nucleophiles to form quaternary stereocentres with good yield and enantioselectivity under mild conditions in the presence of a range of functional groups. These couplings, which probably proceed via a radical pathway, provide access to an array of useful families of organic compounds, including intermediates in the total synthesis of two natural products, (–)-eburnamonine and madindoline A.A wide variety of bioactive molecules contain stereogenic quaternary carbons, and developing methods for the construction of these stereocentres continues to be an active area of research. Now, it has been shown that a nickel-catalysed enantioconvergent coupling of tertiary alkyl electrophiles with alkenylmetal nucleophiles—which probably proceeds via a radical pathway—can form and set quaternary stereocentres efficiently under mild conditions.

In response to genotoxic stress, the tumor suppressor p53 acts as a transcription factor by regulating the expression of genes critical for cancer prevention. Mutations in the gene encoding p53 are associated with cancer development. PRIMA-1 and eprenetapopt (APR-246/PRIMA-1 MET ) are small molecules that are converted into the biologically active compound, methylene quinuclidinone (MQ), shown to reactivate mutant p53 by binding covalently to cysteine residues. Here, we investigate the structural basis of mutant p53 reactivation by MQ based on a series of high-resolution crystal structures of cancer-related and wild-type p53 core domains bound to MQ in their free state and in complexes with their DNA response elements. Our data demonstrate that MQ binds to several cysteine residues located at the surface of the core domain. The structures reveal a large diversity in MQ interaction modes that stabilize p53 and its complexes with DNA, leading to a common global effect that is pertinent to the restoration of non-functional p53 proteins. The tumor suppressor p53 is mutated in more than half of human cancers and the compound methylene quinuclidinone (MQ) was shown to reactivate p53 mutants by binding covalently to cysteine residues. Here, the authors present crystal structures of wild-type and cancer related p53 mutant core domains bound to MQ alone and in complex with their DNA response elements and observe that MQ is bound to several cysteine residues located at the surface of the core domain.

Electronic skins have received increasing attention in biomedical areas. Current efforts about electronic skins are focused on the development of multifunctional materials to improve their performance. Here, the authors propose a novel natural‐synthetic polymers composite structural color hydrogel film with high stretchability, flexibility, conductivity, and superior self‐reporting ability to construct ideal multiple‐signal bionic electronic skins. The composite hydrogel film is prepared by using the mixture of polyacrylamide (PAM), silk fibroin (SF), poly(3,4‐ethylenedioxythiophene):poly (4‐styrene sulfonate) (PEDOT:PSS, PP), and graphene oxide (GO) to replicate colloidal crystal templates and construct inverse opal scaffolds, followed by subsequent acid treatment. Due to these specific structures and components, the resultant film is imparted with vivid structural color and high conductivity while retaining the composite hydrogel's original stretchability and flexibility. The authors demonstrate that the composite hydrogel film has obvious color variation and electromechanical properties during the stretching and bending process, which could thus be utilized as a multi‐signal response electronic skin to realize real‐time color sensing and electrical response during human motions. These features indicate that the proposed composite structural color hydrogel film can widen the practical value of bionic electronic skins. A stretchable and conductive composite structural color hydrogel film with superior self‐reporting ability can be utilized as an intelligent multiple‐signal bionic electronic skin. The composite hydrogel film exhibits obvious color and electrical variation during the stretching and bending process, which makes it feasible to realize real‐time color sensing and electrical response during human motions.

The development of transistors with high gain is essential for applications ranging from switching elements and drivers to transducers for chemical and biological sensing. Organic transistors have become well-established based on their distinct advantages, including ease of fabrication, synthetic freedom for chemical functionalization, and the ability to take on unique form factors. These devices, however, are largely viewed as belonging to the low-end of the performance spectrum. Here we present organic electrochemical transistors with a transconductance in the mS range, outperforming transistors from both traditional and emerging semiconductors. The transconductance of these devices remains fairly constant from DC up to a frequency of the order of 1 kHz, a value determined by the process of ion transport between the electrolyte and the channel. These devices, which continue to work even after being crumpled, are predicted to be highly relevant as transducers in biosensing applications. Although organic transistors have many advantages, they are not typically known for their high performance. Khodagholy et al . report the fabrication of organic electrochemical transistors that combine high transconductance with mechanical flexibility, and are attractive for biosensor applications.

Mycobacterium tuberculosis is a major human pathogen and the causative agent for the pulmonary disease, tuberculosis (TB). Current treatment programs to combat TB are under threat due to the emergence of multi-drug and extensively-drug resistant TB. As part of our efforts towards the discovery of new anti-tubercular leads, a number of potent tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide (THPP) and N-benzyl-6',7'-dihydrospiro[piperidine-4,4'-thieno[3,2-c]pyran] (Spiro) analogues were recently identified against Mycobacterium tuberculosis and Mycobacterium bovis BCG through a high-throughput whole-cell screening campaign. Herein, we describe the attractive in vitro and in vivo anti-tubercular profiles of both lead series. The generation of M. tuberculosis spontaneous mutants and subsequent whole genome sequencing of several resistant mutants identified single mutations in the essential mmpL3 gene. This 'genetic phenotype' was further confirmed by a 'chemical phenotype', whereby M. bovis BCG treated with both the THPP and Spiro series resulted in the accumulation of trehalose monomycolate. In vivo efficacy evaluation of two optimized THPP and Spiro leads showed how the compounds were able to reduce >2 logs bacterial cfu counts in the lungs of infected mice.

Melanoma, a lethal type of cancer originating from melanocytes, is the leading cause of death among skin cancers. While surgical excision of the lesions is the primary treatment for melanoma, not all cases are candidates for surgical procedures. New treatments and complementary options are necessary, given the increasing diagnosis rate. In the present study, a norcantharidin-containing nanoemulsion was developed and evaluated in vivo using a syngeneic graft murine model. Norcantharidin is the demethylated analog of cantharidin, known for its anticancer properties. Our model contemplates surgical excision surgery simulating the standard treatment and the role of the nanoemulsion as a potential adjuvant therapy. We observed a significant decrease in the growth rate of the melanoma lesion in the treated groups compared to the control group, both at the 20th and 30th days of treatment. Moreover, we evaluated the drug bioavailability in serum samples, and the results showed that norcantharidin was detectable in a range of 0.1 to 0.18 mg/mL in the treated groups. Furthermore, histopathological analysis was performed on the amputated tumors, where significant differences were found regarding size, mitosis rate, lymphocytic infiltration, and multispectral quantitative image analysis compared to the control group. If more clinical studies are conducted, the norcantharidin-containing nanoemulsion could be a potential alternative or adjuvant therapy. Topical nanosystems can become or complement standard therapies, which is needed as melanoma affects not only in terms of mortality but also the patient’s morbidity and life quality.

The efficacy of systemic chemotherapy for hepatocellular carcinoma (HCC) is predominantly hampered by low accumulation in tumor tissue and the high systemic toxicity of anticancer drugs. In this study, we designed an in situ drug-loaded injectable thermosensitive hydrogel system for the simultaneous delivery of norcantharidin-loaded nanoparticles (NCTD-NPs) and doxorubicin (Dox) via intratumoral administration to HCC tumors. NCTD-NPs were prepared by the thin film dispersion method using PCEC polymers as the carrier. Then, NCTD-NPs and Dox were co-encapsulated in a thermosensitive hydrogel based on Pluronic F127 (PF127) to construct a dual drug-loaded hydrogel system. The rheological properties of the drug-loaded hydrogel were studied using a rheometer. Drug release of the drug-loaded hydrogel and cytotoxicity in HepG2 cells were evaluated in vitro. An H22 tumor-bearing mice model was used to assess the in vivo antitumor activity of the drug-loaded hydrogel via intratumoral administration. The prepared drug-loaded hydrogel exhibited good thermal-sensitive properties, which remained liquid at room temperature and rapidly transformed into a non-flowing gel at body temperature, and released the drugs in a sustained manner. In vitro studies revealed that the drug-loaded hydrogel exhibited remarkable antiproliferative activity in HepG2 cells compared to free drugs. In vivo antitumor efficacy experiments showed that the drug-loaded hydrogel significantly suppressed tumor growth, alleviated side effects, and prolonged the survival time of mice bearing H22 tumors compared to the other groups. Moreover, immunohistochemical staining revealed that the expression of Ki-67 and CD31 in the drug-loaded hydrogel group was significantly lower than that in the other groups (P < 0.05), indicating that the drug-loaded hydrogel effectively inhibited tumor proliferation and angiogenesis. The formulated hybrid thermosensitive hydrogel system with sustained drug release and enhanced therapeutic efficacy was demonstrated to be a promising strategy for the local-regional treatment of HCC via intratumoral administration.

The wearable electronic skin with high sensitivity and self-power has shown increasing prospects for applications such as human health monitoring, robotic skin, and intelligent electronic products. In this work, we introduced and demonstrated a design of highly sensitive, self-powered, and wearable electronic skin based on a pressure-sensitive nanofiber woven fabric sensor fabricated by weaving PVDF electrospun yarns of nanofibers coated with PEDOT. Particularly, the nanofiber woven fabric sensor with multi-leveled hierarchical structure, which significantly induced the change in contact area under ultra-low load, showed combined superiority of high sensitivity (18.376 kPa −1 , at ~100 Pa), wide pressure range (0.002–10 kPa), fast response time (15 ms) and better durability (7500 cycles). More importantly, an open-circuit voltage signal of the PPNWF pressure sensor was obtained through applying periodic pressure of 10 kPa, and the output open-circuit voltage exhibited a distinct switching behavior to the applied pressure, indicating the wearable nanofiber woven fabric sensor could be self-powered under an applied pressure. Furthermore, we demonstrated the potential application of this wearable nanofiber woven fabric sensor in electronic skin for health monitoring, human motion detection, and muscle tremor detection.

The combination of ABT-199, a BCL-2 inhibitor, and Vorinostat, a histone deacetylase inhibitor, holds great potential in colorectal cancer therapy due to their synergistic effects. However, their poor solubility and bioavailability present challenges for effective treatment. This study aimed to co-encapsulate these drugs in poly(lactic-co-glycolic acid) nanoparticles to enhance stability, control drug release, and preserve their synergistic anti-proliferative effects in colorectal cancer cells. This study initially focused on evaluating the anti-proliferative activity of free ABT-199 and Vorinostat in HT-29 and HCT116 colorectal cancer cells. The drugs demonstrated potent cytotoxic effects, with Vorinostat exhibiting IC 50 values of 1.32 µM in HT-29 cells and 2.04 µM in HCT116 cells, while ABT-199 displayed IC 50 values of 4.04 µM and 5.49 µM, respectively. To investigate the interaction between ABT-199 and Vorinostat, the combination index was calculated using the Chou-Talalay method. The analysis revealed strong synergism between the drugs in both cell lines, with CI values consistently below 1 across all tested molar ratios. The most pronounced synergy was observed at a 1:1 molar ratio, which exhibited the lowest CI values. Building on these results, ABT-199-loaded nanoparticles (ABT-NPs), Vorinostat-loaded nanoparticles (VOR-NPs), and dual-loaded nanoparticles (DLNPs) were formulated using the nanoprecipitation method. ABT-NPs and VOR-NPs had sizes of 210.6 ± 6.2 nm and 202.5 ± 5.6 nm, with encapsulation efficiencies of 73.2 ± 4.81% and 86.4 ± 5.5%, respectively. The DLNPs, which co-encapsulated both drugs at a 1:2 molar ratio, exhibited a size of 210 ± 7.3 nm and maintained good stability. Cytotoxicity studies revealed that both ABT-NPs and VOR-NPs retained comparable anti-proliferative effects to the free drugs, with IC 50 values close to those of their unencapsulated counterparts. Furthermore, DLNPs enhanced the anti-proliferative effect, significantly increased the apoptotic cells as measured by flow cytometry which was coincided with an increasing caspase-3 activity in both HT-29 and HCT116 cells, indicating an enhanced apoptotic response.