Transport mechanism and pharmacology of the human GlyT1.

The glycine transporter 1 (GlyT1) plays a crucial role in the regulation of both inhibitory and excitatory neurotransmission by removing glycine from the synaptic cleft. Given its close association with glutamate/glycine co-activated NMDA receptors (NMDARs), GlyT1 has emerged as a central target for the treatment of schizophrenia, which is often linked to hypofunctional NMDARs. Here, we report the cryo-EM structures of GlyT1 bound with substrate glycine and drugs ALX-5407, SSR504734, and PF-03463275. These structures, captured at three fundamental states of the transport cycle-outward-facing, occluded, and inward-facing-enable us to illustrate a comprehensive blueprint of the conformational change associated with glycine reuptake. Additionally, we identified three specific pockets accommodating drugs, providing clear insights into the structural basis of their inhibitory mechanism and selectivity. Collectively, these structures offer significant insights into the transport mechanism and recognition of substrate and anti-schizophrenia drugs, thus providing a platform to design small molecules to treat schizophrenia.

Structural insight into the allosteric inhibition of human sodium-calcium exchanger NCX1 by XIP and SEA0400.

Sodium-calcium exchanger proteins influence calcium homeostasis in many cell types and participate in a wide range of physiological and pathological processes. Here, we elucidate the cryo-EM structure of the human Na+/Ca2+ exchanger NCX1.3 in the presence of a specific inhibitor, SEA0400. Conserved ion-coordinating residues are exposed on the cytoplasmic face of NCX1.3, indicating that the observed structure is stabilized in an inward-facing conformation. We show how regulatory calcium-binding domains (CBDs) assemble with the ion-translocation transmembrane domain (TMD). The exchanger-inhibitory peptide (XIP) is trapped within a groove between the TMD and CBD2 and predicted to clash with gating helices TMs1/6 at the outward-facing state, thus hindering conformational transition and promoting inactivation of the transporter. A bound SEA0400 molecule stiffens helix TM2ab and affects conformational rearrangements of TM2ab that are associated with the ion-exchange reaction, thus allosterically attenuating Ca2+-uptake activity of NCX1.3.

Kainate receptor modulation by NETO2.

Glutamate-gated kainate receptors are ubiquitous in the central nervous system of vertebrates, mediate synaptic transmission at the postsynapse and modulate transmitter release at the presynapse1-7. In the brain, the trafficking, gating kinetics and pharmacology of kainate receptors are tightly regulated by neuropilin and tolloid-like (NETO) proteins8-11. Here we report cryo-electron microscopy structures of homotetrameric GluK2 in complex with NETO2 at inhibited and desensitized states, illustrating variable stoichiometry of GluK2-NETO2 complexes, with one or two NETO2 subunits associating with GluK2. We find that NETO2 accesses only two broad faces of kainate receptors, intermolecularly crosslinking the lower lobe of ATDA/C, the upper lobe of LBDB/D and the lower lobe of LBDA/C, illustrating how NETO2 regulates receptor-gating kinetics. The transmembrane helix of NETO2 is positioned proximal to the selectivity filter and competes with the amphiphilic H1 helix after M4 for interaction with an intracellular cap domain formed by the M1-M2 linkers of the receptor, revealing how rectification is regulated by NETO2.

High-yield atmospheric water capture via bioinspired material segregation.

Transforming atmospheric water vapor into liquid form can be a way to supply water to arid regions for uses such as drinking water, thermal management, and hydrogen generation. Many current methods rely on solid sorbents that cycle between capture and release at slow rates. We envision a radically different approach where water is transformed and directly captured into a liquid salt solution that is suitable for subsequent distillation or other processing using existing methods. In contrast to other methods utilizing hydrogels as sorbents, we do not store water within hydrogels-we use them as a transport medium. Inspired by nature, we capture atmospheric water through a hydrogel membrane "skin" at an extraordinarily high rate of 5.50 kgm[Formula: see text]d[Formula: see text] at a low humidity of 35%. and up to 16.9 kgm[Formula: see text]d[Formula: see text] at higher humidities. For a drinking-water application, calculated performance of a hypothetical one-square-meter device shows that water could be supplied to two to three people in arid environments. This work is a significant step toward providing new resources and possibilities to water-scarce regions.

Structural insights into the allosteric effects of the antiepileptic drug topiramate on the CaV2.3 channel.

The R-type voltage-gated calcium channel CaV2.3 is predominantly located in the presynapse and is implicated in distinct types of epileptic seizures. It has consequently emerged as a molecular target in seizure treatment. Here, we determined the cryo-EM structure of the CaV2.3-α2δ1-ß1 complex in the topiramate-bound state at a 3.0 Å resolution. We provide a snapshot of the binding site of topiramate, a widely prescribed antiepileptic drug, on a voltage-gated ion channel. The binding site is located at an intracellular juxtamembrane hydrophilic cavity. Further structural analysis revealed that topiramate may allosterically facilitate channel inactivation. These findings provide fundamental insights into the mechanism underlying the inhibitory effect of topiramate on CaV and NaV channels, elucidating a previously unseen modulator binding site and thus pointing toward a route for the development of new drugs.

Quantifying the trade-off between stiffness and permeability in hydrogels.

Hydrogels have a distinct combination of mechanical and water-transport behaviors. As hydrogels stiffen when they de-swell, they become less permeable. Here, we combine de Gennes' semi-dilute polymer theory with the Kozeny-Carman equation to develop a simple, succinct scaling law describing the relationship between mechanical stiffness and hydraulic permeability where permeability scales with stiffness to the -8/9 power. We find a remarkably close agreement between the scaling law and experimental results across four different polymer families with varied crosslinkings. This inverse relationship establishes a fundamental trade-off between permeability and stiffness.

Correction: Quantifying the trade-off between stiffness and permeability in hydrogels.

Correction for 'Quantifying the trade-off between stiffness and permeability in hydrogels' by Yiwei Gao et al., Soft Matter, 2022, 18, 7735-7740, https://doi.org/10.1039/D2SM01215D.

Hierarchical Self-Assembly of Adhesive and Conductive Gels with Anion-Coordinated Triple Helicate Junctions.

The fabrication of anion-coordinated assemblies into functional soft materials remains a major challenge. To this end, four C2 -symmetric anion-binding ligands equipped with ortho-phenylene-bridged bis(urea) and amine or amide ends were designed, which generated A2 L3 triple helical architectures upon self-assembly with phosphate ions. Hierarchical intermolecular hydrogen bonds among the terminal amine/amide groups and urea moieties resulted in the formation of functional gels. The obtained gels were further applied for conductive adhesion between different surfaces, displaying excellent flexibility and selective wettability. The viscoelastic gels constructed from anion-coordinated assemblies described in this work represent the first example of a new class of anion-coordination-driven smart materials.

Scaling laws to predict humidity-induced swelling and stiffness in hydrogels.

From pasta to biological tissues to contact lenses, gel and gel-like materials inherently soften as they swell with water. In dry, low-relative-humidity environments, these materials stiffen as they de-swell with water. Here, we use semi-dilute polymer theory to develop a simple power-law relationship between hydrogel elastic modulus and swelling. From this relationship, we predict hydrogel stiffness or swelling at arbitrary relative humidities. Our close predictions of properties of hydrogels across three different polymer mesh families at varying crosslinking densities and relative humidities demonstrate the validity and generality of our understanding. This predictive capability enables more rapid material discovery and selection for hydrogel applications in varying humidity environments.

Transport mechanism of presynaptic high-affinity choline uptake by CHT1.

Choline is a vital nutrient and a precursor for the biosynthesis of essential metabolites, including acetylcholine (ACh), that play a central role in fetal development, especially in the brain. In cholinergic neurons, the high-affinity choline transporter (CHT1) provides an extraordinarily efficient reuptake mechanism to reutilize choline derived from intrasynaptical ACh hydrolysis and maintain ACh synthesis in the presynapse. Here, we determined structures of human CHT1 in three discrete states: the outward-facing state bound with the competitive inhibitor hemicholinium-3 (HC-3); the inward-facing occluded state bound with the substrate choline; and the inward-facing apo open state. Our structures and functional characterizations elucidate how the inhibitor and substrate are recognized. Moreover, our findings shed light on conformational changes when transitioning from an outward-facing to an inward-facing state and establish a framework for understanding the transport cycle, which relies on the stabilization of the outward-facing state by a short intracellular helix, IH1.

Antibody-drug conjugates for non-small cell lung cancer: Advantages and challenges in clinical translation.

Lung cancer is the leading cause of cancer death, with non-small cell lung cancer (NSCLC) accounting for approximately 85 % of all lung cancers and having a poor treatment and prognosis. Conventional clinical chemotherapy and immunotherapy are challenged by systemic toxicity and drug resistance, so researchers are increasingly focusing on antibody-drug conjugate (ADC), an innovative concept combining chemotherapy and targeted therapy, in which a drug selectively binds to antigens on the surface of a tumor cell via antibodies, which internalize the ADC, and then transfers the ADC to the lysosome via the endosomes to degrade the drug and kill the tumor cell. Despite the promising nature of ADCs, no ADC product for any indication including NSCLC has been approved for marketing by the FDA to date. In this review, we summarize the main advantages of ADCs and discuss in depth the design of the most desirable ADCs for NSCLC therapy. In addition to preclinical studies, we focus on the current state of clinical research on ADCs as interventions for the treatment of NSCLC by summarizing real-time clinical trial data from ClinicalTrials.gov, and reasonably speculate on the direction of the design of future generations of ADCs.

A Multi-Resolution Denoising Method for Low-Dose CT Based on the Reconstruction of Wavelet High-Frequency Channel.

Computed tomography (CT) is widely applied in contemporary clinic. Due to the radiation risks carried by X-rays, the imaging and post-processing methods of low-dose CT (LDCT) become popular topics in academia and industrial community. Generally, LDCT presents strong noise and artifacts, while existing algorithms cannot completely overcome the blurring effects and meantime reduce the noise. The proposed method enables CT extend to independent frequency channels by wavelet transformation, then two separate networks are established for low-frequency denoising and high-frequency reconstruction. The clean signals from high-frequency channel are reconstructed through channel translation, which is essentially effective in preserving detailed structures. The public dataset from Mayo Clinic was used for model training and testing. The experiments showed that the proposed method achieves a better quantitative result (PSNR: 37.42dB, SSIM: 0.8990) and details recovery visually, which demonstrates our framework can better restore the detailed features while significantly suppressing the noise.

Honghua Xiaoyao tablet combined with estradiol improves ovarian function in D-galactose-induced aging mice by reducing apoptosis and affecting the release of reproductive hormones: an in vivo study.

Context: It is very necessary to delay ovarian aging and prevent age-related health problems. The active ingredient in Honghua Xiaoyao tablet (HHXYT) has the effects of anti-oxidation, anti-inflammation, immune regulation and so on. Objective: To explore the effect and mechanism of Honghua Xiaoyao tablet on aging model mice. Materials and methods: The aging model was established by intraperitoneal injection of D-galactose in model mice. The mice in the HHXYT-L,M,H group were given 0.3 g/kg, 0.6 g/kg and 1.2 g/kg Honghua Xiaoyao tablet suspension respectively, and the HHXYT-M + E2 group was given 0.6 g/kg HHXYT +0.13 mg/kg estradiol valerate for 30 days. In this study, ELISA, HE, Western blot, IH and TUNEL were used. Results: HHXYT + E2 can improve the gonadal index, estrous cycle of aging mice. In HHXYT-M + E2 group, the level of FSH and LH decreased, while E2 and AMH increased significantly. The number of growing follicles in HHXYT-M + E2 group increased, which was better than that of HHXYT alone. Western blot results showed that HHXYT-M + E2 group decreased the expression of Bax, cleaved-Parp, cleaved-Casp-3 and CytC molecules and increased the expression of Bcl-2 in ovarian tissue. FSHR expression decreased in model group and increased in HHXYT group. TUNEL staining showed that the number of apoptotic cells in HHXYT group was reduced, and the HHXYT-M + E2 group was the most significantly. Discussion and conclusion: HHXYT can improve the level of sex hormones and increase the number of growing follicles in aging mice. HHXYT-M + E2 group has the best effect, and its mechanism may be related to reducing ovarian granulosa cell apoptosis.

Whole-Liver Based Deep Learning for Preoperatively Predicting Overall Survival in Patients with Hepatocellular Carcinoma.

Survival prediction is crucial for treatment decision making in hepatocellular carcinoma (HCC). We aimed to build a fully automated artificial intelligence system (FAIS) that mines whole-liver information to predict overall survival of HCC. We included 215 patients with preoperative contrast-enhance CT imaging and received curative resection from a hospital in China. The cohort was randomly split into developing and testing subcohorts. The FAIS was constructed with convolutional layers and full-connected layers. Cox regression loss was used for training. Models based on clinical and/or tumor-based radiomics features were built for comparison. The FAIS achieved C-indices of 0.81 and 0.72 for the developing and testing sets, outperforming all the other three models. In conclusion, our study suggest that more important information could be mined from whole liver instead of only the tumor. Our whole-liver based FAIS provides a non-invasive and efficient overall survival prediction tool for HCC before the surgery.

Suppressor of cytokine signaling 3 inhibits breast tumor kinase activation of STAT3.

Breast tumor kinase (Brk) was originally isolated from a human metastatic breast tumor, but also is found expressed in other epithelial tumors and in a subset of normal epithelia. Brk is a tyrosine kinase and its expression in breast carcinoma has been linked to tumor progression. The signal transducer and activator of transcription 3 (STAT3) is one of the substrate targets of Brk, and elevated tyrosine phosphorylation of STAT3 is known to contribute to oncogenesis. Conventional activation of STAT3 occurs in response to cytokine stimulation of Janus tyrosine kinases (JAK). One of the negative regulators discovered in cytokine signaling of the JAK-STAT pathway is the suppressor of cytokine signaling 3 (SOCS3). In this report we describe the finding that SOCS3 can also inhibit the unconventional target, Brk. Investigation of the mechanism by which SOCS3 inhibits Brk reveals the SOCS3 protein binds to Brk primarily via its SH2 domain, and its main inhibitory effect is mediated by the SOCS3 kinase inhibitory region (KIR). SOCS3 has only a modest effect on promoting Brk degradation, and this requires the C-terminal SOCS box domain. SOCS3 is the only known inhibitor of Brk, and knowledge of the mechanisms by which SOCS3 inhibits Brk may lead to methods that block Brk in cancer progression.

The beneficial effects of astragaloside IV on ameliorating diabetic kidney disease.

Diabetic kidney disease (DKD) has become the major cause of chronic kidney disease or end-stage renal disease. There is still a need for innovative treatment strategies for preventing, arresting, treating, and reversing DKD, and a plethora of scientific evidence has revealed that Chinese herbal monomers can attenuate DKD in multiple ways. Astragaloside IV (AS-IV) is one of the active ingredients of Astragalus membranaceus and was selected as a chemical marker in the Chinese Pharmacopeia for quality control purposes. An increasing amount of studies indicate that AS-IV is a promising novel drug for the treatment of DKD. AS-IV has been shown to improve DKD by combating oxidative stress, attenuating endoplasmic reticulum stress, regulating calcium homeostasis, alleviating inflammation, improving vascular function, improving epithelial to mesenchymal transition and so on. This review briefly summarizes the pathogenesis of DKD, systematically reviews the mechanisms by which AS-IV improves DKD, and aims to facilitate related pharmacological research and development to promote the utilization of Chinese herbal monomers in DKD.

Mining Whole-liver Information with Deep Learning for Preoperatively Predicting HCC Recurrence-free Survival.

Hepatocellular carcinoma (HCC) is globally a leading cause of cancer death. Non-invasive pre-operative prediction of HCC recurrence-free survival (RFS) after resection is essential but remains challenging. Previous models based on medical imaging focus only on tumor area while neglecting the whole liver condition. In fact, HCC patients usually suffer from chronic liver diseases which also hamper the patient survival. This work aims to develop a novel convolutional neural network (CNN) to mine whole-liver information from contrast-enhanced computed tomography (CECT) to predict RFS after hepatic resection in HCC. Our proposed RFSNet takes liver regions from CECT as input, and outputs a risk score for each patient. Cox proportional-hazards loss was applied for model training. A total of 215 patients with primary HCC and treated with hepatic resection were included for analysis. Patients were randomly split into developing subcohort and testing subcohort by 4:1. The developing subcohort was further split into the training subcohort and validation subcohort for model training. Baseline models were built with tumor region, radiomics features and/or clinical features the same as previous tumor-based approaches. Results showed that RFSNet achieved the best performance with concordance-indinces (CIs) of 0.88 and 0.65 for the developing and testing subcohorts, respectively. Adding clinical features did not improve RFSNet. Our findings suggest that the proposed RFSNet based on whole liver is able to extract more valuable information concerning RFS prognosis compared to features from only tumor and the clinical indicators.

Architecture and autoinhibitory mechanism of the plasma membrane Na+/H+ antiporter SOS1 in Arabidopsis.

Salt-overly-sensitive 1 (SOS1) is a unique electroneutral Na+/H+ antiporter at the plasma membrane of higher plants and plays a central role in resisting salt stress. SOS1 is kept in a resting state with basal activity and activated upon phosphorylation. Here, we report the structures of SOS1. SOS1 forms a homodimer, with each monomer composed of transmembrane and intracellular domains. We find that SOS1 is locked in an occluded state by shifting of the lateral-gate TM5b toward the dimerization domain, thus shielding the Na+/H+ binding site. We speculate that the dimerization of the intracellular domain is crucial to stabilize the transporter in this specific conformation. Moreover, two discrete fragments and a residue W1013 are important to prevent the transition of SOS1 to an alternative conformational state, as validated by functional complementation assays. Our study enriches understanding of the alternate access model of eukaryotic Na+/H+ exchangers.

Molecular insights into the gating mechanisms of voltage-gated calcium channel CaV2.3.

High-voltage-activated R-type CaV2.3 channel plays pivotal roles in many physiological activities and is implicated in epilepsy, convulsions, and other neurodevelopmental impairments. Here, we determine the high-resolution cryo-electron microscopy (cryo-EM) structure of human CaV2.3 in complex with the α2δ1 and ß1 subunits. The VSDII is stabilized in the resting state. Electrophysiological experiments elucidate that the VSDII is not required for channel activation, whereas the other VSDs are essential for channel opening. The intracellular gate is blocked by the W-helix. A pre-W-helix adjacent to the W-helix can significantly regulate closed-state inactivation (CSI) by modulating the association and dissociation of the W-helix with the gate. Electrostatic interactions formed between the negatively charged domain on S6II, which is exclusively conserved in the CaV2 family, and nearby regions at the alpha-interacting domain (AID) and S4-S5II helix are identified. Further functional analyses indicate that these interactions are critical for the open-state inactivation (OSI) of CaV2 channels.

Increasing fragmentation and squeezing of coastal wetlands: Status, drivers, and sustainable protection from the perspective of remote sensing.

Coastal wetlands are of great ecological and economic value but face significant degradation and losses because of human activities. Nevertheless, the changes in spatiotemporal landscape patterns, which have occurred as a result of coastal wetland losses, have not been well documented under the rapid urbanization in coastal zones. In this study, an algorithm based on periodic tidal inundations and full time-series indices was developed to map the detailed status and trends in the coastal wetlands in Fujian Province from 1994 to 2018 by using more than archived 5000 Landsat images. The results showed that in 2018, there were 1136.56 km2 of coastal wetlands along the coast of Fujian with an overall accuracy of 95.63%, which were mainly distributed in estuaries and bays. These coastal wetlands consisted of tidal flats, low marshes, and high marshes with proportions of 84.91%, 13.05%, and 2.04%, respectively. An unprecedented loss of coastal wetlands has occurred in Fujian Province, with an annual rate of 15.44 km2/a from 1994 to 2018. Many coastal wetlands were reclaimed, dredged, and converted into inland areas for aquaculture ponds, ports, and built-up areas in different urbanization periods, which has led to a great loss of coastal spaces with an area of 476.87 km2. The interplay between the loss of coastal wetlands and seaward urbanization will lead to severe fragmentation and squeezing effects in the coastal zone and will weaken the coastal protection from marine disasters that is provided by coastal wetlands. Therefore, we conceived two conceptional frameworks for sustainable coastal protection based on the current situations of the coastal communities to provide a trade-off between economic development and the protection of coastal developing countries in the world.